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5. The β-Secretase BACE1 in Alzheimer’s Disease

Author

Hampel, Harald, Vassar, Robert, De Strooper, Bart, Hardy, John, Willem, Michael, Singh, Neeraj, Zhou, John, Yan, Riqiang, Vanmechelen, Eugeen, De Vos, Ann, Nisticò, Robert, Corbo, Massimo, Imbimbo, Bruno Pietro, Streffer, Johannes, Voytyuk, Iryna, Timmers, Maarten, Tahami Monfared, Amir Abbas, Irizarry, Michael, Albala, Bruce, Koyama, Akihiko, Watanabe, Naoto, Kimura, Teiji, Yarenis, Lisa, Lista, Simone, Kramer, Lynn, and Vergallo, Andrea

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Brain Disorders, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Humans, Mice, Mice, Knockout, Alzheimer’s disease, BACE1 inhibitors, Biomarkers, Clinical trials, Soluble amyloid, Synaptic, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (Aβ), including Aβ42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aβ in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.

Published
2021

6. Integrative metabolomics science in Alzheimer’s disease: Relevance and future perspectives

Author

Lista, Simone, González-Domínguez, Raúl, López-Ortiz, Susana, González-Domínguez, Álvaro, Menéndez, Héctor, Martín-Hernández, Juan, Lucia, Alejandro, Emanuele, Enzo, Centonze, Diego, Imbimbo, Bruno P., Triaca, Viviana, Lionetto, Luana, Simmaco, Maurizio, Cuperlovic-Culf, Miroslava, Mill, Jericha, Li, Lingjun, Mapstone, Mark, Santos-Lozano, Alejandro, and Nisticò, Robert

Published
2023
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10. Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer's disease trials.

Author

Abanto, Jesus, Dwivedi, Alok K, Imbimbo, Bruno P, and Espay, Alberto J

Subjects
ALZHEIMER'S disease, BIOMARKERS, MONOCLONAL antibodies, COGNITION disorders, AMYLOID
Abstract

Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z -standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: −0.55; 95% CI: −0.89, −0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: −0.16; 95% CI: −0.26, −0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ–PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers

Author

Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaut, Vergallo, Andrea, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Ávila, Jesús, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Caruso, Giuseppe, Castrillo†, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Corbo, Massimo, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giacobini, Ezio, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Hänisch, Britta, Herholz, Karl, Hernandez, Felix, Imbimbo, Bruno P., Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J., Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lemercier, Pablo, Llavero, Francisco, Lorenceau, Jean, Lucía, Alejandro, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O’bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Valenzuela, Pedro L., Vellas, Bruno, Verdooner, Steven R., Villain, Nicolas, Giudici, Kelly Virecoulon, Watling, Mark, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Zugaza, José L., Zetterberg, Henrik, and Blennow, Kaj

Published
2020
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14. Recalibrating the Risk-Benefit Profiles of Lecanemab and Donanemab: Scales, Immunoreactivity, and Changes in Amyloid-β42.

Author

Espay, Alberto J., Herrup, Karl, Imbimbo, Bruno P., Kepp, Kasper P., and Daly, Timothy

Subjects
LECANEMAB, ALZHEIMER'S disease, CEREBROSPINAL fluid, COGNITION, REPORTING of diseases
Abstract

Three recent anti-amyloid-β antibody trials for Alzheimer's disease reported similar effect sizes, used non-reactive saline as placebo, and showed large numbers of adverse events including imaging anomalies (ARIA) that correlate with cognitive changes. Conversely, all previous antibody trials were less reactive and pronounced ineffective. We argue that these observations point to unblinding bias, inflating apparent efficacy and thus altering the risk-benefit balance. Further, we highlight data demonstrating that beyond reducing amyloid, monoclonal antibodies increase monomeric amyloid-β42 in cerebrospinal fluid, which may explain potential benefits. We should recalibrate the efficacy of these antibodies and devote more resources into strategies beyond removing amyloid. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Reversible Cognitive Frailty, Dementia, and All-Cause Mortality. The Italian Longitudinal Study on Aging

Author

Scafato, Emanuele, Farchi, Gino, Galluzzo, Lucia, Gandin, Claudia, Capurso, Antonio, Panza, Francesco, Solfrizzi, Vincenzo, Lepore, Vito, Livrea, Paolo, Motta, Luciano, Carnazzo, Giuseppe, Motta, Massimo, Bentivegna, Prospera, Bonaiuto, Salvatore, Cruciani, Guido, Postacchini, Demetrio, Inzitari, Domenico, Amaducci, Luigi, Di Carlo, Antonio, Baldereschi, Marzia, Gandolfo, Carlo, Conti, Massimo, Canal, Nicola, Franceschi, Massimo, Scarlato, Guglielmo, Candelise, Livia, Scapini, Elio, Rengo, Franco, Abete, Pasquale, Cacciatore, Francesco, Enzi, Giuliano, Battistin, Leontino, Sergi, Giuseppe, Crepaldi, Gaetano, Maggi, Stefania, Minicuci, Nadia, Noale, Marianna, Grigoletto, Francesco, Perissinotto, Egle, Carbonin, Pierugo, Seripa, Davide, Lozupone, Madia, Imbimbo, Bruno P., D'Amato, Angela, Tortelli, Rosanna, Schilardi, Andrea, Daniele, Antonio, Sabbà, Carlo, and Logroscino, Giancarlo

Published
2017
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30. Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Author

Lozupone, Madia, Imbimbo, Bruno Pietro, Balducci, Claudia, Lo Vecchio, Filomena, Bisceglia, Paola, Latino, Raffaela Rita, Leone, Maurizio, Dibello, Vittorio, Solfrizzi, Vincenzo, Greco, Antonio, Daniele, Antonio, Watling, Mark, Seripa, Davide, and Panza, Francesco

Abstract

Human apolipoprotein E (apoE) is a 299‐amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood–brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aβ) deposition, and tau‐mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE‐mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE‐targeting approaches being developed as potential AD therapies. Intracisternal adeno‐associated viral‐mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti‐APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE–Aβ interaction inhibitors produced positive results in transgenic AD mouse models. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging

Author

Solfrizzi, Vincenzo, Scafato, Emanuele, Frisardi, Vincenza, Seripa, Davide, Logroscino, Giancarlo, Kehoe, Patrick G., Imbimbo, Bruno P., Baldereschi, Marzia, Crepaldi, Gaetano, Di Carlo, Antonio, Galluzzo, Lucia, Gandin, Claudia, Inzitari, Domenico, Maggi, Stefania, Pilotto, Alberto, Panza, Francesco, and for the Italian Longitudinal Study on Aging Working Group

Published
2013
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34. MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

Author

Vergallo, Andrea, Lista, Simone, group, INSIGHT-preAD study, Lucía, Alejandro, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O'Bryant, Sid E, Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Initiative, Alzheimer Precision Medicine, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S, Sporns, Olaf, Toschi, Nicola, Valenzuela, Pedro L, Vellas, Bruno, Verdooner, Steven R, Villain, Nicolas, Giudici, Kelly Virecoulon, Bakardjian, Hovagim, Watling, Mark, Welikovitch, Lindsay A, Woodcock, Janet, Younesi, Erfan, Zugaza, José L, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Zhao, Yuhai, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lemercier, Pablo, Lamari, Foudil, Levy, Marcel, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Teipel, Stefan J, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaut, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Ávila, Jesús, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L, Bokde, Arun L W, Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Caruso, Giuseppe, Castrillo, Juan, Ceravolo, Roberto, Chiesa, Patrizia A, Corbo, Massimo, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L, Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A, Garaci, Francesco, Lukiw, Walter J, Geerts, Hugo, Giacobini, Ezio, Giorgi, Filippo S, Goetzl, Edward J, Graziani, Manuela, Haberkamp, Marion, Hänisch, Britta, Herholz, Karl, Hernandez, Felix, Imbimbo, Bruno P, Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J, Kim, Seung H, Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Llavero, Francisco, Lorenceau, Jean, Ministre de l'Enseignement Supérieur, de la Recherche et de l'Innovation (France), Sorbonne Université, AXA Research Fund, Fondation partenariale, Fondation pour la Recherche sur Alzheimer, Investissement d’Avenir French program, Vergallo, Andrea [0000-0002-0208-6384], Apollo - University of Cambridge Repository, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Louisiana State University (LSU), University of Rostock, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CATI Multicenter Neuroimaging Platform (CATI), Service de médecine nucléaire [CHU Pitié-Salpétrière], Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Department of Psychiatry, Psychosomatic Medicine and Psychotherapy [Goethe Universität], Goethe-Universität Frankfurt am Main, HAL-SU, Gestionnaire, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Service de Médecine nucléaire [CHU Pitié-Salpétrière], Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France, Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Apolipoprotein E, Aging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease, miRNAs plasma concentrations, Alzheimer's Disease, amyloid-β (Aβ)-positron emission tomography (Aβ-PET), Prognostic markers, 0302 clinical medicine, Medicine, Psychology, Aetiology, education.field_of_study, MicroARNs, Settore FIS/07, amyloid, Brain, Pathophysiology, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Alzheimer's disease (AD), Public Health and Health Services, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MiRNA, medicine.medical_specialty, 18F-fluorodeoxyglucose-PET (18F-FDG-PET), BIOMARKERS, Neurociencias, Clinical Sciences, Molecular neuroscience, Predictive markers, Article, VESICLES, lcsh:RC321-571, 03 medical and health sciences, Memory, Clinical Research, Alzheimer Disease, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Genetics, Humans, education, Biological Psychiatry, Prevention, Memory, MiRNA, Alzheimer, biological markers, amyloid, 030104 developmental biology, Endocrinology, Cross-Sectional Studies, Positron-Emission Tomography, CELLS, Dementia, diagnostic imaging [Alzheimer Disease], INSIGHT-preAD study group, 030217 neurology & neurosurgery, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 0301 basic medicine, genetics [Alzheimer Disease], Pilot Projects, Neurodegenerative, Medicine and Health Sciences, 2.1 Biological and endogenous factors, genetics [MicroRNAs], MIR-125B, screening and diagnosis, PLASMA, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Detection, Real-time polymerase chain reaction, Neurological, medicine.symptom, biological markers, Biotechnology, EXPRESSION, Population, metabolism [Amyloid beta-Peptides], Asymptomatic, Salud mental, Cellular and Molecular Neuroscience, ADULT, Fluorodeoxyglucose F18, Internal medicine, Acquired Cognitive Impairment, ddc:610, Allele, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, diagnostic imaging [Brain], Psiquiatría, Amyloid beta-Peptides, Enfermedad de alzheimer, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurosciences, Alzheimer Precision Medicine Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, MicroRNAs, metabolism [Brain], Alzheimer, business, Psychiatric disorders
Abstract

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and F-fluorodeoxyglucose-PET (F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways., “Investissement d’Avenir” (ANR-10-AIHU-06) French program. The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. CATI is a French neuroimaging platform funded by the French Plan Alzheimer (available at http://cati-neuroimaging.com). A.V. is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. H.H. is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. At Sorbonne University he was supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer

Published
2021

43. A path toward precision medicine for neuroinflammatory mechanisms in Alzheimer's disease

Author

Hampel, Harald, Caraci, Filippo, Cuello, A. Claudio, Caruso, Giuseppe, Nisticó, Robert, Corbo, Massimo, Baldacci, Filippo, Toschi, Nicola, Garaci, Francesco, Chiesa, Patrizia A., Verdooner, Steven R., Akman Anderson, Leyla, Hernández, Félix, Ávila, Jesús, Emanuele, Enzo, Valenzuela, Pedro L., Lucía, Alejandro, Watling, Mark, Imbimbo, Bruno P., Vergallo, Andrea, Sorbonne Université, Fondation pour la Recherche sur Alzheimer, and AXA Research Fund

Subjects
Neuroinflammation, Neuroinflammatory pathways, Precision medicine, Microglia, Systems biology, Alzheimer’s disease, Biomarkers, Antiinflammatory therapy
Abstract

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine. Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. HH is an employee of Eisai Inc. During his previous work (until April 2019), he was supported by the AXA Research Fund, the Fondation partenariale Sorbonne Université and the Fondation pour la Recherche sur Alzheimer, Paris, France

Published
2020

46. Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers

Author

Vergallo, Andrea, primary, Lista, Simone, additional, Lemercier, Pablo, additional, Chiesa, Patrizia A., additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Potier, Marie-Claude, additional, Habert, Marie-Odile, additional, Baldacci, Filippo, additional, Cavedo, Enrica, additional, Caraci, Filippo, additional, Dubois, Bruno, additional, Hampel, Harald, additional, Bakardjian, Hovagim, additional, Benali, Habib, additional, Bertin, Hugo, additional, Bonheur, Joel, additional, Boukadida, Laurie, additional, Boukerrou, Nadia, additional, Chiesa, Patrizia, additional, Colliot, Olivier, additional, Dubois, Marion, additional, Epelbaum, Stéphane, additional, Gagliardi, Geoffroy, additional, Genthon, Remy, additional, Houot, Marion, additional, Kas, Aurélie, additional, Lamari, Foudil, additional, Levy, Marcel, additional, Metzinger, Christiane, additional, Mochel, Fanny, additional, Nyasse, Francis, additional, Poisson, Catherine, additional, Revillon, Marie, additional, Santos, Antonio, additional, Andrade, Katia Santos, additional, Sole, Marine, additional, Surtee, Mohmed, additional, de Schotten, Michel Thiebaut, additional, Vergallo, Andrea, additional, Younsi, Nadjia, additional, Afshar, Mohammad, additional, Aguilar, Lisi Flores, additional, Akman-Anderson, Leyla, additional, Arenas, Joaquín, additional, Ávila, Jesús, additional, Babiloni, Claudio, additional, Batrla, Richard, additional, Benda, Norbert, additional, Black, Keith L., additional, Bokde, Arun L.W., additional, Bonuccelli, Ubaldo, additional, Broich, Karl, additional, Cacciola, Francesco, additional, Caruso, Giuseppe, additional, Castrillo†, Juan, additional, Ceravolo, Roberto, additional, Corbo, Massimo, additional, Corvol, Jean-Christophe, additional, Cuello, Augusto Claudio, additional, Cummings, Jeffrey L., additional, Depypere, Herman, additional, Duggento, Andrea, additional, Emanuele, Enzo, additional, Escott-Price, Valentina, additional, Federoff, Howard, additional, Ferretti, Maria Teresa, additional, Fiandaca, Massimo, additional, Frank, Richard A., additional, Garaci, Francesco, additional, Geerts, Hugo, additional, Giacobini, Ezio, additional, Giorgi, Filippo S., additional, Goetzl, Edward J., additional, Graziani, Manuela, additional, Haberkamp, Marion, additional, Hänisch, Britta, additional, Herholz, Karl, additional, Hernandez, Felix, additional, Imbimbo, Bruno P., additional, Kapogiannis, Dimitrios, additional, Karran, Eric, additional, Kiddle, Steven J., additional, Kim, Seung H., additional, Koronyo, Yosef, additional, Koronyo-Hamaoui, Maya, additional, Langevin, Todd, additional, Lehéricy, Stéphane, additional, Llavero, Francisco, additional, Lorenceau, Jean, additional, Lucía, Alejandro, additional, Mango, Dalila, additional, Mapstone, Mark, additional, Neri, Christian, additional, Nisticò, Robert, additional, O’bryant, Sid E., additional, Palermo, Giovanni, additional, Perry, George, additional, Ritchie, Craig, additional, Rossi, Simone, additional, Saidi, Amira, additional, Santarnecchi, Emiliano, additional, Schneider, Lon S., additional, Sporns, Olaf, additional, Toschi, Nicola, additional, Valenzuela, Pedro L., additional, Vellas, Bruno, additional, Verdooner, Steven R., additional, Villain, Nicolas, additional, Giudici, Kelly Virecoulon, additional, Watling, Mark, additional, Welikovitch, Lindsay A., additional, Woodcock, Janet, additional, Younesi, Erfan, additional, and Zugaza, José L., additional

Published
2020
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