186 results on '"Heneka, Michael T."'
Search Results
2. Perivascular space enlargement accelerates in ageing and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study
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Menze, Inga, Bernal, Jose, Kaya, Pinar, Aki, Çağla, Pfister, Malte, Geisendörfer, Jonas, Yakupov, Renat, Coello, Roberto Duarte, Valdés-Hernández, Maria d. C., Heneka, Michael T., Brosseron, Frederic, Schmid, Matthias C., Glanz, Wenzel, Incesoy, Enise I., Butryn, Michaela, Rostamzadeh, Ayda, Meiberth, Dix, Peters, Oliver, Preis, Lukas, Lammerding, Dominik, Gref, Daria, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Lohse, Andrea, Hetzer, Stefan, Schneider, Anja, Fliessbach, Klaus, Kimmich, Okka, Vogt, Ina R., Wiltfang, Jens, Bartels, Claudia, Schott, Björn H., Hansen, Niels, Dechent, Peter, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Laske, Christoph, Munk, Matthias H., Sanzenbacher, Carolin, Hinderer, Petra, Scheffler, Klaus, Spottke, Annika, Roy-Kluth, Nina, Lüsebrink, Falk, Neumann, Katja, Wardlaw, Joanna, Jessen, Frank, Schreiber, Stefanie, Düzel, Emrah, and Ziegler, Gabriel
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- 2024
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3. Inflammatory aspects of Alzheimer’s disease
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Botella Lucena, Pablo and Heneka, Michael T.
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- 2024
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4. The endotoxin hypothesis of Alzheimer’s disease
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Brown, Guy C. and Heneka, Michael T.
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- 2024
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5. Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?
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Lista, Simone, Imbimbo, Bruno P., Grasso, Margherita, Fidilio, Annamaria, Emanuele, Enzo, Minoretti, Piercarlo, López-Ortiz, Susana, Martín-Hernández, Juan, Gabelle, Audrey, Caruso, Giuseppe, Malaguti, Marco, Melchiorri, Daniela, Santos-Lozano, Alejandro, Imbimbo, Camillo, Heneka, Michael T., and Caraci, Filippo
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- 2024
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6. Impact of COVID‐19 on the Onset and Progression of Alzheimer's Disease and Related Dementias: A Roadmap for Future Research
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Gordon, Marcia N, Heneka, Michael T, Le Page, Lydia M, Limberger, Christian, Morgan, David, Tenner, Andrea J, Terrando, Niccolò, Willette, Auriel A, and Willette, Sara A
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Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Acquired Cognitive Impairment ,Infectious Diseases ,Clinical Research ,Neurodegenerative ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Coronaviruses ,Emerging Infectious Diseases ,Social Determinants of Health ,Dementia ,Behavioral and Social Science ,Alzheimer's Disease ,Coronaviruses Disparities and At-Risk Populations ,2.1 Biological and endogenous factors ,Neurological ,Good Health and Well Being ,Alzheimer Disease ,COVID-19 ,Caregivers ,Cognitive Dysfunction ,Communicable Disease Control ,Humans ,Alzheimer's risk factor ,caregiver burden ,delerium ,longitudinal cohort ,systemic inflammation ,SARS-CoV-2 ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
COVID-19 causes lasting neurological symptoms in some survivors. Like other infections, COVID-19 may increase risk of cognitive impairment. This perspective highlights four knowledge gaps about COVID-19 that need to be filled to avoid this possible health issue. The first is the need to identify the COVID-19 symptoms, genetic polymorphisms and treatment decisions associated with risk of cognitive impairment. The second is the absence of model systems in which to test hypotheses relating infection to cognition. The third is the need for consortia for studying both existing and new longitudinal cohorts in which to monitor long term consequences of COVID-19 infection. A final knowledge gap discussed is the impact of the isolation and lack of social services brought about by quarantine/lockdowns on people living with dementia and their caregivers. Research into these areas may lead to interventions that reduce the overall risk of cognitive decline for COVID-19 survivors.
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- 2022
7. Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study
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Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, Kolbe, Carl-Christian, Wolfsgruber, Steffen, Santarelli, Francesco, Häsler, Lisa M., McManus, Róisín, Ising, Christina, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Schneider, Luisa-Sophie, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Görß, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupow, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Spottke, Annika, Ramirez, Alfredo, Mengel, David, Synofzik, Matthis, Jucker, Mathias, Latz, Eicke, Jessen, Frank, Wagner, Michael, and Heneka, Michael T.
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- 2023
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8. Exploring the ATN classification system using brain morphology
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Heinzinger, Nils, Maass, Anne, Berron, David, Yakupov, Renat, Peters, Oliver, Fiebach, Jochen, Villringer, Kersten, Preis, Lukas, Priller, Josef, Spruth, Eike Jacob, Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Bartels, Claudia, Jessen, Frank, Maier, Franziska, Glanz, Wenzel, Buerger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Killimann, Ingo, Göerß, Doreen, Laske, Christoph, Munk, Matthias H., Spottke, Annika, Roy, Nina, Heneka, Michael T., Brosseron, Frederic, Dobisch, Laura, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Wolfsgruber, Steffen, Kleineidam, Luca, Schmid, Matthias, Berger, Moritz, Düzel, Emrah, and Ziegler, Gabriel
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- 2023
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9. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
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Jansen, Iris E., van der Lee, Sven J., Gomez-Fonseca, Duber, de Rojas, Itziar, Dalmasso, Maria Carolina, Grenier-Boley, Benjamin, Zettergren, Anna, Mishra, Aniket, Ali, Muhammad, Andrade, Victor, Bellenguez, Céline, Kleineidam, Luca, Küçükali, Fahri, Sung, Yun Ju, Tesí, Niccolo, Vromen, Ellen M., Wightman, Douglas P., Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Amouyel, Philippe, Athanasiu, Lavinia, Bahrami, Shahram, Bailly, Henri, Belbin, Olivia, Bergh, Sverre, Bertram, Lars, Biessels, Geert Jan, Blennow, Kaj, Blesa, Rafael, Boada, Mercè, Boland, Anne, Buerger, Katharina, Carracedo, Ángel, Cervera-Carles, Laura, Chene, Geneviève, Claassen, Jurgen A. H. R., Debette, Stephanie, Deleuze, Jean-Francois, de Deyn, Peter Paul, Diehl-Schmid, Janine, Djurovic, Srdjan, Dols-Icardo, Oriol, Dufouil, Carole, Duron, Emmanuelle, Düzel, Emrah, Fladby, Tormod, Fortea, Juan, Frölich, Lutz, García-González, Pablo, Garcia-Martinez, Maria, Giegling, Ina, Goldhardt, Oliver, Gobom, Johan, Grimmer, Timo, Haapasalo, Annakaisa, Hampel, Harald, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herukka, Sanna-Kaisa, Holstege, Henne, Jarholm, Jonas, Kern, Silke, Knapskog, Anne-Brita, Koivisto, Anne M., Kornhuber, Johannes, Kuulasmaa, Teemu, Lage, Carmen, Laske, Christoph, Leinonen, Ville, Lewczuk, Piotr, Lleó, Alberto, de Munain, Adolfo López, Lopez-Garcia, Sara, Maier, Wolfgang, Marquié, Marta, Mol, Merel O., Montrreal, Laura, Moreno, Fermin, Moreno-Grau, Sonia, Nicolas, Gael, Nöthen, Markus M., Orellana, Adelina, Pålhaugen, Lene, Papma, Janne M., Pasquier, Florence, Perneczky, Robert, Peters, Oliver, Pijnenburg, Yolande A. L., Popp, Julius, Posthuma, Danielle, Pozueta, Ana, Priller, Josef, Puerta, Raquel, Quintela, Inés, Ramakers, Inez, Rodriguez-Rodriguez, Eloy, Rujescu, Dan, Saltvedt, Ingvild, Sanchez-Juan, Pascual, Scheltens, Philip, Scherbaum, Norbert, Schmid, Matthias, Schneider, Anja, Selbæk, Geir, Selnes, Per, Shadrin, Alexey, Skoog, Ingmar, Soininen, Hilkka, Tárraga, Lluís, Teipel, Stefan, Tijms, Betty, Tsolaki, Magda, Van Broeckhoven, Christine, Van Dongen, Jasper, van Swieten, John C., Vandenberghe, Rik, Vidal, Jean-Sébastien, Visser, Pieter J., Vogelgsang, Jonathan, Waern, Margda, Wagner, Michael, Wiltfang, Jens, Wittens, Mandy M. J., Zetterberg, Henrik, Zulaica, Miren, van Duijn, Cornelia M., Bjerke, Maria, Engelborghs, Sebastiaan, Jessen, Frank, Teunissen, Charlotte E., Pastor, Pau, Hiltunen, Mikko, Ingelsson, Martin, Andreassen, Ole A., Clarimón, Jordi, Sleegers, Kristel, Ruiz, Agustín, Ramirez, Alfredo, Cruchaga, Carlos, Lambert, Jean-Charles, and van der Flier, Wiesje
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- 2022
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10. Passive anti-amyloid β immunotherapy in Alzheimer's disease—opportunities and challenges.
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Heneka, Michael T, Morgan, David, and Jessen, Frank
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ALZHEIMER'S disease , *ADUCANUMAB , *DISEASE progression , *PATIENTS' rights , *LECANEMAB - Abstract
With the advent of the first disease-modifying, anti-amyloid β-directed passive immunotherapy for Alzheimer's disease, questions arise who, when, and how to treat. This paper describes shortly the pathogenic basis of and preclinical data, which have, more than two decades ago, initiated the development of this vaccination therapy. We discuss clinical trial results of aducanumab, lecanemab, and donanemab. We also review appropriate use recommendations of these novel treatments on patient selection and safety monitoring. Furthermore, estimations of numbers of patient who will qualify for treatment regarding inclusion and exclusion criteria and estimations on readiness of health-care systems for identifying the right patients and for providing the treatment are reported. In our view, we are experiencing a fundamental shift from syndrome-based Alzheimer's dementia care to early, biomarker-guided treatment of Alzheimer's disease. This shift requires substantial adjustments of infrastructure and resources, but also holds promise of eventually achieving substantial slowing of disease progression and delaying dementia. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.
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Soch, Joram, Richter, Anni, Kizilirmak, Jasmin M, Schütze, Hartmut, Ziegler, Gabriel, Altenstein, Slawek, Brosseron, Frederic, Dechent, Peter, Fliessbach, Klaus, Freiesleben, Silka Dawn, Glanz, Wenzel, Gref, Daria, Heneka, Michael T, Hetzer, Stefan, Incesoy, Enise I, Kilimann, Ingo, Kimmich, Okka, Kleineidam, Luca, Kuhn, Elizabeth, and Laske, Christoph
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FUNCTIONAL magnetic resonance imaging ,ALZHEIMER'S disease ,DISEASE risk factors ,PROGNOSIS ,YOUNG adults - Abstract
Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional MRI activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive ageing. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analysed subsequent memory functional MRI data from individuals with SCD, MCI and AD dementia as well as healthy controls and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-centre DELCODE study (n = 468). Based on the individual participants' whole-brain functional MRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity and APOE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to healthy controls, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ɛ4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients. [ABSTRACT FROM AUTHOR]
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- 2024
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12. p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function
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Perea, Juan R., Bolós, Marta, Cuadros, Raquel, García, Esther, García-Escudero, Vega, Hernández, Félix, McManus, Róisín M., Heneka, Michael T., and Avila, Jesús
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- 2022
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13. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease
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Franzmeier, Nicolai, Düzel, Emrah, Jessen, Frank, Buerger, Katharina, Levin, Johannes, Duering, Marco, Dichgans, Martin, Haass, Christian, Suárez-Calvet, Marc, Fagan, Anne M, Paumier, Katrina, Benzinger, Tammie, Masters, Colin L, Morris, John C, Perneczky, Robert, Janowitz, Daniel, Catak, Cihan, Wolfsgruber, Steffen, Wagner, Michael, Teipel, Stefan, Kilimann, Ingo, Ramirez, Alfredo, Rossor, Martin, Jucker, Mathias, Chhatwal, Jasmeer, Spottke, Annika, Boecker, Henning, Brosseron, Frederic, Falkai, Peter, Fliessbach, Klaus, Heneka, Michael T, Laske, Christoph, Nestor, Peter, Peters, Oliver, Fuentes, Manuel, Menne, Felix, Priller, Josef, Spruth, Eike J, Franke, Christiana, Schneider, Anja, Kofler, Barbara, Westerteicher, Christine, Speck, Oliver, Wiltfang, Jens, Bartels, Claudia, Caballero, Miguel Ángel Araque, Metzger, Coraline, Bittner, Daniel, Weiner, Michael, Lee, Jae-Hong, Salloway, Stephen, Danek, Adrian, Goate, Alison, Schofield, Peter R, Bateman, Randall J, and Ewers, Michael
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Clinical Trials and Supportive Activities ,Brain Disorders ,Aging ,Basic Behavioral and Social Science ,Dementia ,Neurosciences ,Behavioral and Social Science ,Acquired Cognitive Impairment ,Clinical Research ,Alzheimer's Disease ,Neurodegenerative ,Biomedical Imaging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Alzheimer Disease ,Amyloid beta-Protein Precursor ,Brain Mapping ,Cognitive Dysfunction ,Female ,Frontal Lobe ,Functional Laterality ,Humans ,Imaging ,Three-Dimensional ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Mutation ,Nerve Net ,Presenilin-1 ,Presenilin-2 ,Alzheimer's disease ,cognitive reserve ,resting state connectivity ,memory ,dementia biomarkers ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
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- 2018
14. Vaccination with (1–11)E2 in alum efficiently induces an antibody response to β-amyloid without affecting brain β-amyloid load and microglia activation in 3xTg mice
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Mantile, Francesca, Capasso, Angelo, Villacampa, Nadia, Donnini, Maria, Liguori, Giovanna L., Constantin, Gabriela, De Berardinis, Piergiuseppe, Heneka, Michael T., and Prisco, Antonella
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- 2021
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15. The putative contribution of cellular senescence to driving tauopathies.
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Karabag, Deniz, Heneka, Michael T., and Ising, Christina
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ALZHEIMER'S disease , *TAU proteins , *CENTRAL nervous system diseases , *CELLULAR aging , *TAUOPATHIES , *CELL cycle - Abstract
Cellular senescence is cell type and inducer specific. Therefore, senescent cells are not easily recognizable, and multiple markers should be used for their identification. Tauopathies are characterized by an increased presence of senescent cells, including microglia, astrocytes, oligodendrocytes, and neurons. Senescence is detected not only in culture and animal models but also in human postmortem tauopathy brains. Multiple phenotypes characterizing senescent cells, such as cell cycle arrest markers, DNA damage, and the release of a senescence-associated secretory profile (SASP), are present in tauopathies. The release of a SASP by senescent cells contributes to the inflammatory phenotype seen in tauopathies and may involve the activation of the NLRP3 inflammasome. Several neurodegenerative disorders, including the most common dementia in humans, Alzheimer's disease, as well as other dementias and movement disorders, show abnormal intracellular accumulation of the microtubule-associated protein tau (MAPT). Most of these diseases are of the elderly. With aging, accumulation of senescent cells can be observed in the central nervous system (CNS). Recent evidence suggests a putative involvement of these senescent cells in the pathology of tauopathies. Thus, elucidating the mechanisms by which senescent cells might contribute to driving tauopathies constitutes an important area of investigation. During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation. [ABSTRACT FROM AUTHOR]
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- 2024
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16. NLRP3‐directed antisense oligonucleotides reduce microglial immunoactivities in vitro.
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Braatz, Charlotte, Komes, Max P., Ravichandran, Kishore Aravind, de Fragas, Matheus Garcia, Griep, Angelika, Schwartz, Stephanie, McManus, Róisín M., and Heneka, Michael T.
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IMMUNOMODULATORS ,ALZHEIMER'S disease ,NATURAL immunity ,MEMORY disorders ,NLRP3 protein - Abstract
Alzheimer's disease (AD) is associated with the cerebral deposition of Amyloid‐β (Aβ) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin‐1β (IL‐1β) and interleukin‐18 (IL‐18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here, we test whether NLRP3‐directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP‐1 cells. NLRP3 mRNA degradation was achieved at 72 h of ASO treatment in primary murine microglia. Consequently, NLRP3‐directed ASOs significantly reduced the levels of cleaved caspase‐1 and mature IL‐1β when microglia were either activated by LPS and nigericin or LPS and Aβ. In human THP‐1 cells NLRP3‐targeted ASOs also significantly reduced the LPS plus nigericin‐ or LPS plus Aβ‐induced release of mature IL‐1β. Together, NLRP3‐directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL‐1β in primary murine microglia and THP‐1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Neuroinflammation in Alzheimer's disease
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Heneka, Michael T, Carson, Monica J, Khoury, Joseph El, Landreth, Gary E, Brosseron, Frederic, Feinstein, Douglas L, Jacobs, Andreas H, Wyss-Coray, Tony, Vitorica, Javier, Ransohoff, Richard M, Herrup, Karl, Frautschy, Sally A, Finsen, Bente, Brown, Guy C, Verkhratsky, Alexei, Yamanaka, Koji, Koistinaho, Jari, Latz, Eicke, Halle, Annett, Petzold, Gabor C, Town, Terrence, Morgan, Dave, Shinohara, Mari L, Perry, V Hugh, Holmes, Clive, Bazan, Nicolas G, Brooks, David J, Hunot, Stéphane, Joseph, Bertrand, Deigendesch, Nikolaus, Garaschuk, Olga, Boddeke, Erik, Dinarello, Charles A, Breitner, John C, Cole, Greg M, Golenbock, Douglas T, and Kummer, Markus P
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Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Brain Disorders ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Prevention ,Neurodegenerative ,Dementia ,Aging ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Inflammatory and immune system ,Alzheimer Disease ,Animals ,Anti-Inflammatory Agents ,Non-Steroidal ,Astrocytes ,Biomarkers ,Brain Injuries ,Clinical Trials as Topic ,Disease Models ,Animal ,Disease Progression ,Humans ,Immunity ,Innate ,Immunization ,Inflammation ,Inflammation Mediators ,Locus Coeruleus ,Microglia ,Nootropic Agents ,Obesity ,Phagocytosis ,Protein Folding ,Risk Factors ,Severity of Illness Index ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
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- 2015
18. Improving 3D convolutional neural network comprehensibility via interactive visualization of relevance maps: evaluation in Alzheimer’s disease
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Dyrba, Martin, Hanzig, Moritz, Altenstein, Slawek, Bader, Sebastian, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Cantré, Daniel, Dechent, Peter, Dobisch, Laura, Düzel, Emrah, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Haynes, John-Dylan, Heneka, Michael T., Janowitz, Daniel, Keles, Deniz B., Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Metzger, Coraline D., Munk, Matthias H., Perneczky, Robert, Peters, Oliver, Preis, Lukas, Priller, Josef, Rauchmann, Boris, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H., Spottke, Annika, Spruth, Eike J., Weber, Marc-André, Ertl-Wagner, Birgit, Wagner, Michael, Wiltfang, Jens, Jessen, Frank, and Teipel, Stefan J.
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- 2021
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19. SFRP1 modulates astrocyte-to-microglia crosstalk in acute and chronic neuroinflammation
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Rueda-Carrasco, Javier, Martin-Bermejo, María Jesús, Pereyra, Guadalupe, Mateo, María Inés, Borroto, Aldo, Brosseron, Frederic, Kummer, Markus P, Schwartz, Stephanie, López-Atalaya, José P, Alarcon, Balbino, Esteve, Pilar, Heneka, Michael T, and Bovolenta, Paola
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- 2021
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20. Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals.
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Sannemann, Lena, Bartels, Claudia, Brosseron, Frederic, Buerger, Katharina, Fliessbach, Klaus, Freiesleben, Silka Dawn, Frommann, Ingo, Glanz, Wenzel, Heneka, Michael T., Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Lammerding, Dominik, Laske, Christoph, Munk, Matthias H.J., Perneczky, Robert, Peters, Oliver, Priller, Josef, Rauchmann, Boris-Stephan, and Rostamzadeh, Ayda
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AMYLOID ,ALZHEIMER'S disease ,COGNITIVE interviewing ,CEREBROSPINAL fluid ,COGNITION disorders - Abstract
Background: The NIA-AA Research Framework on Alzheimer's disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective: To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods: We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ
42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42 /ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions: The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology. [ABSTRACT FROM AUTHOR]- Published
- 2024
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21. Inferior Frontal Sulcal Hyperintensities on Brain MRI Are Associated with Amyloid Positivity beyond Age—Results from the Multicentre Observational DELCODE Study.
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Dörner, Marc, Seebach, Katharina, Heneka, Michael T., Menze, Inga, von Känel, Roland, Euler, Sebastian, Schreiber, Frank, Arndt, Philipp, Neumann, Katja, Hildebrand, Annkatrin, John, Anna-Charlotte, Tyndall, Anthony, Kirchebner, Johannes, Tacik, Pawel, Jansen, Robin, Grimm, Alexander, Henneicke, Solveig, Perosa, Valentina, Meuth, Sven G., and Peters, Oliver
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AMYLOID ,MAGNETIC resonance imaging ,OPTIMISM ,ALZHEIMER'S disease ,MINI-Mental State Examination - Abstract
Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer's disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05–3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57–2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00–1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26–0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice
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Tzeng, Te-Chen, Hasegawa, Yuto, Iguchi, Risa, Cheung, Amy, Caffrey, Daniel R., Thatcher, Elizabeth Jeanne, Mao, Wenjie, Germain, Gail, DePaula Tamburro, Nelsy, Okabe, Shigeo, Heneka, Michael T., Latz, Eicke, Futai, Kensuke, and Golenbock, Douglas T.
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- 2018
23. Dysregulation of TLR5 and TAM Ligands in the Alzheimer’s Brain as Contributors to Disease Progression
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Herrera-Rivero, Marisol, Santarelli, Francesco, Brosseron, Frederic, Kummer, Markus P., and Heneka, Michael T.
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- 2019
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24. Innate immune activation in neurodegenerative diseases.
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Castro-Gomez, Sergio and Heneka, Michael T.
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NEURODEGENERATION , *PATTERN perception receptors , *ALZHEIMER'S disease , *AMYOTROPHIC lateral sclerosis , *TAUOPATHIES , *TAU proteins , *MOVEMENT disorders , *FRONTOTEMPORAL lobar degeneration - Abstract
Activation of the innate immune system following pattern recognition receptor binding has emerged as one of the major pathogenic mechanisms in neurodegenerative disease. Experimental, epidemiological, pathological, and genetic evidence underscores the meaning of innate immune activation during the prodromal as well as clinical phases of several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Importantly, innate immune activation and the subsequent release of inflammatory mediators contribute mechanistically to other hallmarks of neurodegenerative diseases such as aberrant proteostatis, pathological protein aggregation, cytoskeleton abnormalities, altered energy homeostasis, RNA and DNA defects, and synaptic and network disbalance and ultimately to the induction of neuronal cell death. In this review, we discuss common mechanisms of innate immune activation in neurodegeneration, with particular emphasis on the pattern recognition receptors (PRRs) and other receptors involved in the detection of damage-associated molecular patterns (DAMPs). The activation of the innate immune system and subsequent neuroinflammation are common hallmarks of all neurodegenerative diseases. Castro-Gomez and Heneka review the emerging evidence related to receptors implicated in the activation of innate immunity during neurodegenerative processes. They predominantly focus on the role of microglia, PRRs, and other DAMP-sensing receptors in the pathogenesis of Alzheimer's disease, tauopathy, Parkinson's disease, and amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Silencing Apoe with divalent‐siRNAs improves amyloid burden and activates immune response pathways in Alzheimer's disease.
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Ferguson, Chantal M., Hildebrand, Samuel, Godinho, Bruno M. D. C., Buchwald, Julianna, Echeverria, Dimas, Coles, Andrew, Grigorenko, Anastasia, Vangjeli, Lorenc, Sousa, Jacquelyn, McHugh, Nicholas, Hassler, Matthew, Santarelli, Francesco, Heneka, Michael T., Rogaev, Evgeny, and Khvorova, Anastasia
- Abstract
INTRODUCTION: The most significant genetic risk factor for late‐onset Alzheimer's disease (AD) is APOE4, with evidence for gain‐ and loss‐of‐function mechanisms. A clinical need remains for therapeutically relevant tools that potently modulate APOE expression. METHODS: We optimized small interfering RNAs (di‐siRNA, GalNAc) to potently silence brain or liver Apoe and evaluated the impact of each pool of Apoe on pathology. RESULTS: In adult 5xFAD mice, siRNAs targeting CNS Apoe efficiently silenced Apoe expression and reduced amyloid burden without affecting systemic cholesterol, confirming that potent silencing of brain Apoe is sufficient to slow disease progression. Mechanistically, silencing Apoe reduced APOE‐rich amyloid cores and activated immune system responses. DISCUSSION: These results establish siRNA‐based modulation of Apoe as a viable therapeutic approach, highlight immune activation as a key pathway affected by Apoe modulation, and provide the technology to further evaluate the impact of APOE silencing on neurodegeneration. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Inflammasomes in neurological disorders — mechanisms and therapeutic potential.
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Ravichandran, Kishore Aravind and Heneka, Michael T.
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INFLAMMASOMES , *NEUROLOGICAL disorders , *ALZHEIMER'S disease , *AMYOTROPHIC lateral sclerosis , *ENCEPHALITIS - Abstract
Inflammasomes are molecular scaffolds that are activated by damage-associated and pathogen-associated molecular patterns and form a key element of innate immune responses. Consequently, the involvement of inflammasomes in several diseases that are characterized by inflammatory processes, such as multiple sclerosis, is widely appreciated. However, many other neurological conditions, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, stroke, epilepsy, traumatic brain injury, sepsis-associated encephalopathy and neurological sequelae of COVID-19, all involve persistent inflammation in the brain, and increasing evidence suggests that inflammasome activation contributes to disease progression in these conditions. Understanding the biology and mechanisms of inflammasome activation is, therefore, crucial for the development of inflammasome-targeted therapies for neurological conditions. In this Review, we present the current evidence for and understanding of inflammasome activation in neurological diseases and discuss current and potential interventional strategies that target inflammasome activation to mitigate its pathological consequences. Increasing evidence suggests that inflammasome activation contributes to disease progression in a wide variety of neurological conditions. In this Review, Ravichandran and Heneka discuss current understanding of inflammasome activation in neurological disorders and consider interventional strategies that target inflammasome activation. Key points: Inflammasomes are key molecular scaffolds that mediate innate immune responses. Many neurological conditions involve an underlying chronic inflammatory process that worsens the trajectory of these conditions. Increased activation of NLRP3 and other inflammasomes, leading to increases in IL-1β and IL-18 and neuronal damage, is seen in post-mortem brain tissue from people with neurological conditions. Genetic ablation and synthetic inhibition of inflammasomes and inflammasome-associated proteins can ameliorate neurological deficits in rodent models of neurological conditions. Use of inflammasome-targeted therapeutic approaches could improve existing therapeutic strategies for multiple neurological conditions. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Non-target LC-HRMS to Study the Exposome of Mild Cognitive Impairment and Alzheimer's Disease on Cerebrospinal Fluid
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Andújar, Begoña Talvavera, Mary, Arnaud, Cheng, Tiejun, Zaslavsky, Leonid, Bolton, Evan E., Heneka, Michael T., and Schymanski, Emma L.
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liquid chromatography ,cheminformatics ,CSF ,Alzheimer's disease ,High resolution mass spectrometry ,exposomics - Abstract
This is the poster presentation number1142 for the19th Annual International Conference of theMetabolomicsSociety.
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- 2023
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28. Phosphorylation-state dependent intraneuronal sorting of Aβ differentially impairs autophagy and the endo-lysosomal system.
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Kapadia, Akshay, Theil, Sandra, Opitz, Sabine, Villacampa, Nàdia, Beckert, Hannes, Schoch, Susanne, Heneka, Michael. T., Kumar, Sathish, and Walter, Jochen
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AUTOPHAGY ,FLUORESCENT proteins ,CATHEPSIN D ,MICROTUBULE-associated proteins ,MEMBRANE proteins ,RAS oncogenes - Abstract
Progressive accumulation of amyloid-β (Aβ) aggregates in extracellular plaques is a characteristic hallmark of Alzheimer disease (AD). Aβ is also found in intraneuronal deposits and associated with alterations of the endo-lysosomal system and impairment of macroautophagy/autophagy. Here, we assessed the effect of Aβ phosphorylation on neuronal autophagy and the endo-lysosomal pathway. Analysis of APP-PSEN1dE9 transgenic mice revealed a phosphorylation-state dependent intraneuronal accumulation of Aβ species in endo-lysosomal and autophagy-related compartments. Cell biological studies further demonstrate a differential uptake and sorting of phosphorylated Aβ variants in cultured neurons, and phosphorylation-state specific effects of Aβ variants on neuronal autophagy and lysosomal function. While Aβ phosphorylated at serine residue 8 accumulated in autophagosomes, Aβ phosphorylated at serine residue 26 showed efficient transport to lysosomes. The selective sorting of phosphorylated Aβ species caused differential impairment of vesicular transport and lysosomal function associated with neurotoxicity. Thus, the relative occurrence of phosphorylated Aβ species and their intraneuronal accumulation could contribute to AD pathogenesis, and to the commonly observed aberrations of the vesicular transport system already at the early stages of the disease. AD: Alzheimer disease; APP: amyloid beta precursor protein; ATG: autophagy related; Aβ: amyloid-β; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; EEA1: early endosome antigen 1; FA: formic acid; GFP: green fluorescent protein; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP2: microtubule-associated protein 2; nmAβ: non-modified amyloid-β; npAβ: non-phosphorylated amyloid-β; pAβ: phosphorylated amyloid-β; p-Ser26Aβ: amyloid-β phosphorylated at serine residue 26; p-Ser8Aβ: amyloid-β phosphorylated at serine residue 8; RAB: RAB, member RAS oncogene family; RFP: red fluorescent protein; SQSTM1/p62: sequestome 1; YFP: yellow fluorescent protein. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Author Correction: Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
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de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernández, Isabel, Antúnez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Céline, Quintela, Inés, González-Perez, Antonio, Calero, Miguel, Macías, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menéndez-González, Manuel, Royo, Jose Luís, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Mónica, Lage, Carmen, García-González, Pablo, Valero, Sergi, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benussi, Alberto, Rábano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonça, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Pastor, Ana Belén, Espinosa, Ana, Corma-Gómez, Anaïs, Sanabria, Ángela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Kinhult Ståhlbom, Anne, Tybjærg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbatón-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Børge G., Kunkle, Brian W., Charbonnier, Camille, Masullo, Carlo, Martínez Rodríguez, Carmen, Muñoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Grünblatt, Edna, Dardiotis, Efthimios, Düzel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Küçükali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gaël, Selbæk, Geir, Ortega, Gemma, Chêne, Geneviève, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Rosas Allende, Irene, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Jürgen, Buerger, Katharina, Morgan, Kevin, Fließbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitée, Löwenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Bernal Sánchez-Arjona, María, Dalmasso, Maria Carolina, Martínez-Larrad, María Teresa, Arcaro, Marina, Nöthen, Markus M., Fernández-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossù, Paola, Caffarra, Paolo, Dionigi Rossi, Paolo, Sakka, Paraskevi, Mecocci, Patrizia, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hägg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Botne Sando, Sigrid, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Smith, A. David, Saenz, Aldo, Bizzarro, Alessandra, Lauria, Alessandra, Vacca, Alessandro, Solomon, Alina, Anastasiou, Anna, Richardson, Anna, Boland, Anne, Koivisto, Anne, Daniele, Antonio, Greco, Antonio, Marianthi, Arnaoutoglou, McGuinness, Bernadette, Fin, Bertrand, Ferrari, Camilla, Custodero, Carlo, Ferrarese, Carlo, Ingino, Carlos, Mangone, Carlos, Reyes Toso, Carlos, Martínez, Carmen, Cuesta, Carolina, Muchnik, Carolina, Joachim, Catharine, Ortiz, Cecilia, Besse, Céline, Johansson, Charlotte, Zoia, Chiara Paola, Laske, Christoph, Anastasiou, Costas, Palacio, Dana Lis, Politis, Daniel G., Janowitz, Daniel, Craig, David, Mann, David M., Neary, David, Jürgen, Deckert, Daian, Delphine, Belezhanska, Diyana, Kohler, Eduardo, Castaño, Eduardo M., Koutsouraki, Effrosyni, Chipi, Elena, De Roeck, Ellen, Costantini, Emanuele, Vardy, Emma R. L. C., Piras, Fabrizio, Roveta, Fausto, Piras, Federica, Prestia, Federico Ariel, Assogna, Francesca, Salani, Francesca, Sala, Gessica, Lacidogna, Giordano, Novack, Gisela, Wilcock, Gordon, Thonberg, Håkan, Kölsch, Heike, Weber, Heike, Boecker, Henning, Etchepareborda, Ignacio, Piaceri, Irene, Tuomilehto, Jaakko, Lindström, Jaana, Laczo, Jan, Johnston, Janet, Deleuze, Jean-François, Harris, Jenny, Schott, Jonathan M., Priller, Josef, Bacha, Juan Ignacio, Snowden, Julie, Lisso, Julieta, Mihova, Kalina Yonkova, Traykov, Latchezar, Morelli, Laura, Brusco, Luis Ignacio, Rainer, Malik, Takalo, Mari, Bjerke, Maria, Del Zompo, Maria, Serpente, Maria, Sanchez Abalos, Mariana, Rios, Mario, Peltonen, Markku, Herrman, Martin J., Kohler, Matias, Rojo, Matias, Jones, Matthew, Orsini, Michela, Medel, Nancy, Olivar, Natividad, Fox, Nick C., Salvadori, Nicola, Hooper, Nigel M., Galeano, Pablo, Solis, Patricia, Bastiani, Patrizia, Passmore, Peter, Heun, Reinhard, Antikainen, Riitta, Olaso, Robert, Perneczky, Robert, Germani, Sandra, López-García, Sara, Love, Seth, Mehrabian, Shima, Bagnoli, Silvia, Kochen, Silvia, Andreoni, Simona, Teipel, Stefan, Todd, Stephen, Pickering-Brown, Stuart, Natunen, Teemu, Tegos, Thomas, Laatikainen, Tiina, Strandberg, Timo, Polvikoski, Tuomo M., Matoska, Vaclav, Ciullo, Valentina, Cores, Valeria, Solfrizzi, Vincenzo, Lisetti, Viviana, Sevillano, Zulma, Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García-González, P., Gil, S., Guitart, M., González-Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M.T., Marquié, M., Mauleón, A., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J.A., Preckler, S., Quintela, I., Real, L.M., Rosende-Roca, M., Ruiz, A., Sáez, M.E., Sanabria, A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A.D., Alarcón-Martín, E., Alonso, M.D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Bullido, M.J., Burguera, J.A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., del Ser, T., Diez-Fairen, M., Escuela, R., Garrote-Espina, L., Fortea, J., Franco-Macías, E., Frank-García, A., Garcia Madrona, S., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M.A., Lage, C., Legaz, A., Lleó, A., Lopez de Munain, A., López-García, S., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J.L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, Carol, Bresner, Catherine, Grozeva, Detelina, Bellou, Eftychia, Sommerville, Ewen W., Matthews, F., Leonenko, Ganna, Menzies, Georgina, Windle, Gill, Harwood, Janet, Phillips, Judith, Bennett, K., Luckuck, Lauren, Clare, Linda, Woods, Robert, Saad, Salha, Burholt, Vanessa, Kehoe, Patrick Gavin, Garcia-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Pérez-Tur, Jordi, Piñol-Ripoll, Gerard, Lopez de Munain, Adolfo, García-Alberca, Jose María, Bullido, María J., Álvarez, Victoria, Lleó, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sánchez-Valle, Raquel, Serrano-Ríos, Manuel, Orellana, Adelina, Tárraga, Lluís, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimón, Jordi, Boada, Mercè, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., Ruiz, Agustín, Smith, A David, Saenz, Aldo, Bizzarro, Alessandra, Lauria, Alessandra, Vacca, Alessandro, Solomon, Alina, Anastasiou, Anna, Richardson, Anna, Boland, Anne, Koivisto, Anne, Daniele, Antonio, Greco, Antonio, Marianthi, Arnaoutoglou, McGuinness, Bernadette, Fin, Bertrand, Ferrari, Camilla, Custodero, Carlo, Ferrarese, Carlo, Ingino, Carlos, Mangone, Carlos, Reyes Toso, Carlos, Martínez, Carmen, Cuesta, Carolina, Muchnik, Carolina, Joachim, Catharine, Ortiz, Cecilia, Besse, Céline, Johansson, Charlotte, Zoia, Chiara Paola, Laske, Christoph, Anastasiou, Costas, Palacio, Dana Lis, Politis, Daniel G, Janowitz, Daniel, Craig, David, Mann, David M, Neary, David, Jürgen, Deckert, Daian, Delphine, Belezhanska, Diyana, Kohler, Eduardo, Castaño, Eduardo M, Koutsouraki, Effrosyni, Chipi, Elena, De Roeck, Ellen, Costantini, Emanuele, Vardy, Emma R L C, Piras, Fabrizio, Roveta, Fausto, Piras, Federica, Prestia, Federico Ariel, Assogna, Francesca, Salani, Francesca, Sala, Gessica, Lacidogna, Giordano, Novack, Gisela, Wilcock, Gordon, Thonberg, Håkan, Kölsch, Heike, Weber, Heike, Boecker, Henning, Etchepareborda, Ignacio, Piaceri, Irene, Tuomilehto, Jaakko, Lindström, Jaana, Laczo, Jan, Johnston, Janet, Deleuze, Jean-François, Harris, Jenny, Schott, Jonathan M, Priller, Josef, Bacha, Juan Ignacio, Snowden, Julie, Lisso, Julieta, Mihova, Kalina Yonkova, Traykov, Latchezar, Morelli, Laura, Brusco, Luis Ignacio, Rainer, Malik, Takalo, Mari, Bjerke, Maria, Del Zompo, Maria, Serpente, Maria, Sanchez Abalos, Mariana, Rios, Mario, Peltonen, Markku, Herrman, Martin J, Kohler, Matias, Rojo, Matias, Jones, Matthew, Orsini, Michela, Medel, Nancy, Olivar, Natividad, Fox, Nick C, Salvadori, Nicola, Hooper, Nigel M, Galeano, Pablo, Solis, Patricia, Bastiani, Patrizia, Passmore, Peter, Heun, Reinhard, Antikainen, Riitta, Olaso, Robert, Perneczky, Robert, Germani, Sandra, López-García, Sara, Love, Seth, Mehrabian, Shima, Bagnoli, Silvia, Kochen, Silvia, Andreoni, Simona, Teipel, Stefan, Todd, Stephen, Pickering-Brown, Stuart, Natunen, Teemu, Tegos, Thomas, Laatikainen, Tiina, Strandberg, Timo, Polvikoski, Tuomo M, Matoska, Vaclav, Ciullo, Valentina, Cores, Valeria, Solfrizzi, Vincenzo, Lisetti, Viviana, Sevillano, Zulma, Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Corbatón-Anchuelo, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García-González, P., Gil, S., Guitart, M., González-Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M. T., Marquié, M., Mauleón, A., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J. A., Preckler, S., Quintela, I., Real, L. M., Rosende-Roca, M., Ruiz, A., Sáez, M. E., Sanabria, A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A. D., Alarcón-Martín, E., Alonso, M. D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Buiza-Rueda, D., Bullido, M. J., Burguera, J. A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M. J., Clarimón, J., Cruz-Gamero, J. M., de Pancorbo, M. M., Del Ser, T., Diez-Fairen, M., Escuela, R., Garrote-Espina, L., Fortea, J., Franco-Macías, E., Frank-García, A., García-Alberca, J. M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M. A., Lage, C., Legaz, A., Lleó, A., Lopez de Munain, A., López-García, S., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J. L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J. L., Sanchez Del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M. P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, Carol, Bresner, Catherine, Grozeva, Detelina, Bellou, Eftychia, Sommerville, Ewen W, Matthews, F., Leonenko, Ganna, Menzies, Georgina, Windle, Gill, Harwood, Janet, Phillips, Judith, Bennett, K., Luckuck, Lauren, Clare, Linda, Woods, Robert, Saad, Salha, Burholt, Vanessa, Rongve, Arvid, Brussels Heritage Lab, Clinical sciences, Neuroprotection & Neuromodulation, and Neurology
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polygenic risk scores ,Multidisciplinary ,Common variants ,Neuroscience(all) ,neurology ,Medizin ,General Physics and Astronomy ,ddc:500 ,General Chemistry ,Alzheimer's disease ,General Biochemistry, Genetics and Molecular Biology ,RISK STRATIFICATION - Abstract
The original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. CA extern
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- 2023
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30. Zooming in on brain inflammation in Alzheimer's disease.
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Flier, Wiesje M van der and Heneka, Michael T
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GLIAL fibrillary acidic protein , *ENCEPHALITIS , *ALZHEIMER'S disease , *INFLAMMATION , *TRANSLOCATOR proteins - Published
- 2025
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31. A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer's Disease Continuum
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Ersoezlue, Ersin, Perneczky, Robert, Keeser, Daniel, Papazov, Boris, Totzke, Marie, Ballarini, Tommaso, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Tato, Maia, Glanz, Wenzel, Haynes, John Dylan, Heneka, Michael T, Janowitz, Daniel, Kilimann, Ingo, Kleineidam, Luca, Laske, Christoph, Maier, Franziska, Munk, Matthias H, Peters, Oliver, Utecht, Julia, Priller, Josef, Ramirez, Alfredo, Roeske, Sandra, Roy, Nina, Scheffler, Klaus, Schneider, Anja, Schott, Björn H, Spottke, Annika, Spruth, Eike J, Teipel, Stefan, Kurz, Carolin, Unterfeld, Chantal, Wagner, Michael, Wang, Xiao, Wiltfang, Jens, Wolfsgruber, Steffen, Yakupov, Renat, Duezel, Emrah, Jessen, Frank, Rauchmann, Boris-Stephan, group, DELCODE study, Häckert, Jan, Guersel, Selim, Burow, Lena, Koller, Gabriele, and Stoecklein, Sophia
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cognition ,General Neuroscience ,resting-state functional connectivity ,General Medicine ,cognitive reserve ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,Clinical Psychology ,pathology [Alzheimer Disease] ,intrinsic network connectivity ,Neural Pathways ,Humans ,functional MRI ,ddc:610 ,Geriatrics and Gerontology ,Nerve Net ,diagnostic imaging [Brain] ,Alzheimer’s disease - Abstract
Background: Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. Objective: To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer’s disease (ADN). Methods: Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-β)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. Results: CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. Conclusion: Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state.
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- 2023
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32. An immune-cell signature marks the brain in Alzheimer’s disease
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Heneka, Michael T.
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- 2020
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33. Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis
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Kalinin, Sergey, González-Prieto, Marta, Scheiblich, Hannah, Lisi, Lucia, Kusumo, Handojo, Heneka, Michael T., Madrigal, Jose L. M., Pandey, Subhash C., and Feinstein, Douglas L.
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- 2018
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34. Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease
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Brosseron, Frederic, Traschütz, Andreas, Widmann, Catherine N., Kummer, Markus P., Tacik, Pawel, Santarelli, Francesco, Jessen, Frank, and Heneka, Michael T.
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- 2018
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35. Early Changes in Hippocampal Neurogenesis in Transgenic Mouse Models for Alzheimer’s Disease
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Unger, M. S., Marschallinger, J., Kaindl, J., Höfling, C., Rossner, S., Heneka, Michael T., Van der Linden, A., and Aigner, Ludwig
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- 2016
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36. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers
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Suárez‐Calvet, Marc, Kleinberger, Gernot, Araque Caballero, Miguel Ángel, Brendel, Matthias, Rominger, Axel, Alcolea, Daniel, Fortea, Juan, Lleó, Alberto, Blesa, Rafael, Gispert, Juan Domingo, Sánchez‐Valle, Raquel, Antonell, Anna, Rami, Lorena, Molinuevo, José L, Brosseron, Frederic, Traschütz, Andreas, Heneka, Michael T, Struyfs, Hanne, Engelborghs, Sebastiaan, Sleegers, Kristel, Van Broeckhoven, Christine, Zetterberg, Henrik, Nellgård, Bengt, Blennow, Kaj, Crispin, Alexander, Ewers, Michael, and Haass, Christian
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- 2016
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37. Sporadic Use of Antibiotics in Older Adults and the Risk of Dementia: A Nested Case–Control Study Based on German Health Claims Data.
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Rakuša, Elena, Fink, Anne, Tamgüney, Gültekin, Heneka, Michael T., and Doblhammer, Gabriele
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DISEASE risk factors ,OLDER people ,ALZHEIMER'S disease ,ANTIBIOTICS ,CASE-control method ,VASCULAR dementia - Abstract
Background: Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline. Objective: To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer's disease). Methods: We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement. Results: Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14–1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90–0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90–0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90–0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88–0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85–0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92–0.99). Conclusion: Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance. [ABSTRACT FROM AUTHOR]
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- 2023
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38. APOE and immunity: Research highlights.
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Kloske, Courtney M., Barnum, Christopher J., Batista, Andre F., Bradshaw, Elizabeth M., Brickman, Adam M., Bu, Guojun, Dennison, Jessica, Gearon, Mary D., Goate, Alison M., Haass, Christian, Heneka, Michael T., Hu, William T., Huggins, Lenique K. L., Jones, Nahdia S., Koldamova, Radosveta, Lemere, Cynthia A., Liddelow, Shane A., Marcora, Edoardo, Marsh, Samuel E., and Nielsen, Henrietta M.
- Abstract
INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4‐day meeting, presenters illuminated aspects of the cross‐talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development. [ABSTRACT FROM AUTHOR]
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- 2023
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39. The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap.
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Walker, Keenan A., Le Page, Lydia M., Terrando, Niccolò, Duggan, Michael R., Heneka, Michael T., and Bettcher, Brianne M.
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ALZHEIMER'S disease ,DISEASE risk factors ,INFLAMMATION ,THERAPEUTICS ,EVIDENCE gaps - Abstract
Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer's disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer's disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood–brain barrier and other components of the neuro-immune axis in Alzheimer's disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer's disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology. [ABSTRACT FROM AUTHOR]
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- 2023
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40. Cholinergic white matter pathways along the Alzheimer's disease continuum.
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Nemy, Milan, Dyrba, Martin, Brosseron, Frederic, Buerger, Katharina, Dechent, Peter, Dobisch, Laura, Ewers, Michael, Fliessbach, Klaus, Glanz, Wenzel, Goerss, Doreen, Heneka, Michael T, Hetzer, Stefan, Incesoy, Enise I, Janowitz, Daniel, Kilimann, Ingo, Laske, Christoph, Maier, Franziska, Munk, Matthias H, Perneczky, Robert, and Peters, Oliver
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ALZHEIMER'S disease ,WHITE matter (Nerve tissue) ,CHOLINERGIC mechanisms ,MILD cognitive impairment ,COGNITION disorders ,RECEIVER operating characteristic curves - Abstract
Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert. [ABSTRACT FROM AUTHOR]
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- 2023
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41. Relevance of Subjective Cognitive Decline in Older Adults with a First-Degree Family History of Alzheimer's Disease
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Wolfsgruber, Steffen, Kleineidam, Luca, Priller, Josef, Fließbach, Klaus, Schneider, Anja, Wiltfang, Jens, Bartels, Claudia, Jessen, Frank, Maier, Franziska, Düzel, Emrah, Metzger, Coraline, Glanz, Wenzel, Weyrauch, Anne Sophie, Bürger, Katharina, Janowitz, Daniel, Perneczky, Robert, Rauchmann, Boris Stephan, Kilimann, Ingo, Teipel, Stefan, Laske, Christoph, Munk, Matthias H, Roy, Nina, Spottke, Annika, Barkhoff, Miriam, Ramirez, Alfredo, Heneka, Michael T, Brosseron, Frederic, Wagner, Michael, group, DELCODE study, Röske, Sandra, Peters, Oliver, Preis, Lukas, Gref, Daria, Spruth, Eike Jakob, and Altenstein, Slawek
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Male ,family history ,General Neuroscience ,General Medicine ,Neuropsychological Tests ,cerebrospinal fluid ,Psychiatry and Mental health ,Clinical Psychology ,pathology [Alzheimer Disease] ,Cross-Sectional Studies ,cerebrospinal fluid [Biomarkers] ,Alzheimer Disease ,Humans ,Cognitive Dysfunction ,Female ,ddc:610 ,psychology [Cognitive Dysfunction] ,Geriatrics and Gerontology ,subjective cognitive decline ,Alzheimer’s disease ,Biomarkers ,Aged - Abstract
Background: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n = 82 “AD relatives”; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n = 236 healthy controls without FHAD from the DELCODE study. We measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression.
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- 2022
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42. Nonsteroidal Anti-Inflammatory Drugs Repress β-Secretase Gene Promoter Activity by the Activation of PPARγ
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Sastre, Magdalena, Dewachter, Ilse, Rossner, Steffen, Bogdanovic, Nenad, Rosen, Evan, Borghgraef, Peter, Evert, Bernd O., Dumitrescu-Ozimek, Lucia, Thal, Dietmar R., Landreth, Gary, Walter, Jochen, Klockgether, Thomas, van Leuven, Fred, and Heneka, Michael T.
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- 2006
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43. Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: a Comparative Overview
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Brosseron, Frederic, Krauthausen, Marius, Kummer, Markus, and Heneka, Michael T.
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- 2014
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44. Extracellular phosphorylation of the amyloid β‐peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease
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Kumar, Sathish, Rezaei‐Ghaleh, Nasrollah, Terwel, Dick, Thal, Dietmar R, Richard, Mélisande, Hoch, Michael, Mc Donald, Jessica M, Wüllner, Ullrich, Glebov, Konstantin, Heneka, Michael T, Walsh, Dominic M, Zweckstetter, Markus, and Walter, Jochen
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- 2011
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45. Neuroinflammatory processes in Alzheimer’s disease
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Heneka, Michael T., O’Banion, M. Kerry, Terwel, Dick, and Kummer, Markus Peter
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- 2010
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46. Intrinsic Regulation of Brain Inflammatory Responses
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Galea, Elena, Heneka, Michael T., Russo, Cinzia Dello, and Feinstein, Douglas L.
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- 2003
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47. Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction.
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Düzel, Emrah, Ziegler, Gabriel, Berron, David, Maass, Anne, Schütze, Hartmut, Cardenas-Blanco, Arturo, Glanz, Wenzel, Metzger, Coraline, Dobisch, Laura, Reuter, Martin, Spottke, Annika, Brosseron, Frederic, Fliessbach, Klaus, Heneka, Michael T, Laske, Christoph, Peters, Oliver, Priller, Josef, Spruth, Eike Jakob, Ramirez, Alfredo, and Speck, Oliver
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PROTEINS ,AMYLOIDOSIS ,ALZHEIMER'S disease ,NERVE tissue proteins ,HIPPOCAMPUS (Brain) ,CROSS-sectional method ,APOLIPOPROTEINS ,RESEARCH funding ,PEPTIDES - Abstract
We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A-) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A- individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A- groups. After classifying this matched sample for phospho-tau pathology (T-/T+), individuals with A+/T+ were significantly more memory-impaired than A-/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer's disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer's disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function. [ABSTRACT FROM AUTHOR]
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- 2022
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48. Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study
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Brosseron, Frederic, Kolbe, Carl-Christian, Santarelli, Francesco, Carvalho, Stephanie, Antonell, Anna, Castro-Gomez, Sergio, Tacik, Pawel, Namasivayam, Aishwarya Alex, Mangone, Graziella, Schneider, Reinhard, Latz, Eicke, Wüllner, Ullrich, Svenningsson, Per, Sánchez-Valle, Raquel, Molinuevo, José Luis, Corvol, Jean-Christophe, Heneka, Michael T., Hofmann-Apitius, Martin, Springstubbe, Stephan, Fröhlich, Holger, and Publica
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mild cognitive impairment ,inflammation ,Parkinson's disease ,aging ,amyloid ,Biomarker ,tau ,multicenter ,Alzheimer's disease ,cerebrospinal fluid - Abstract
Introduction: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. Methods: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. Results: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. Discussion: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.
- Published
- 2020
49. ApoE4 makes microglia trem2bling.
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Heneka, Michael T.
- Subjects
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APOLIPOPROTEIN E4 , *APOLIPOPROTEIN E , *MOLECULAR interactions , *ALZHEIMER'S disease , *TAU proteins - Abstract
The ApoE-Trem2 pathway links two of the most important genetic risk variants for sporadic Alzheimer's disease. In this issue of Neuron , Gratuze and colleagues 1 report that Trem2 deficiency further aggravates neurodegeneration in tau mutant mice expressing human ApoE4. Together with previous work, this study points to a complex interaction and highlights the need for studying molecular interactions on all human ApoE variants. The ApoE-Trem2 pathway links two of the most important genetic risk variants for sporadic Alzheimer's disease. In this issue of Neuron , Gratuze and colleagues1 report that Trem2 deficiency further aggravates neurodegeneration in tau mutant mice expressing human ApoE4. Together with previous work, this study points to a complex interaction and highlights the need for studying molecular interactions on all human ApoE variants. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
50. Microglial PD‐1 stimulation by astrocytic PD‐L1 suppresses neuroinflammation and Alzheimer's disease pathology.
- Author
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Kummer, Markus P, Ising, Christina, Kummer, Christiane, Sarlus, Heela, Griep, Angelika, Vieira‐Saecker, Ana, Schwartz, Stephanie, Halle, Annett, Brückner, Matthias, Händler, Kristian, Schultze, Joachim L, Beyer, Marc, Latz, Eicke, and Heneka, Michael T
- Subjects
MICROGLIA ,PATHOLOGY ,ALZHEIMER'S disease ,PROGRAMMED death-ligand 1 ,PROGRAMMED cell death 1 receptors ,NEUROINFLAMMATION ,AMYLOID plaque - Abstract
Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune‐cell checkpoint receptor/ligand pair PD‐1/PD‐L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD‐L1 and PD‐1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD‐L1 from astrocytes, which may mediate ectodomain signaling to PD‐1‐expressing microglia. Deletion of microglial PD‐1 evoked an inflammatory response and compromised amyloid‐β peptide (Aβ) uptake. APP/PS1 mice deficient for PD‐1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD‐1/PD‐L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD. SYNOPSIS: Neuroinflammation, a hallmark of Alzheimer's disease (AD), is involved in beta‐amyloid peptide (Aβ) plaque deposition and clearance. Here, the PD‐1/PD‐L1 axis is found as an important pathway for regulating the immune system in the brain, sustaining microglial Aβ uptake and reducing chronic neuroinflammation. Astrocytic PD‐L1 and microglial PD‐1 are upregulated around Aβ plaques in Alzheimer's disease (AD) and APP/PS1 mice.PD‐L1 is secreted in a soluble form by astrocytes in culture.PD‐1 deficiency compromises Aβ phagocytosis and induces an inflammatory response in vitro.Loss of PD‐1 increases Aβ plaque deposition and reduces microglial Aβ uptake in APP/PS1 mice. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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