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Depression is frequent amongst older adults, and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain-derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise-induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti-inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for depression symptoms was performed using the 15-item Geriatric Depression Scale (GDS-15). Results showed that CSF irisin and lipoxin A4 are positively correlated and reduced, with a trend of BDNF reduction, in elderly individuals with depression, similar to observations in patients with dementia. Our findings provide novel insight into shared molecular signatures connecting depression and dementia. This article is protected by copyright. All rights reserved.

About 10 million new cases of dementia develop worldwide each year, of which up to 70% are attributable to Alzheimer's disease (AD). In addition to the widely known symptoms of memory loss and cognitive impairment, AD patients frequently develop non-cognitive symptoms, referred to as behavioral and psychological symptoms of dementia (BPSDs). Sleep disorders are often associated with AD, but mood alterations, notably depression and apathy, comprise the most frequent class of BPSDs. BPSDs negatively affect the lives of AD patients and their caregivers, and have a significant impact on public health systems and the economy. Because treatments currently available for AD are not disease-modifying and mainly aim to ameliorate some of the cognitive symptoms, elucidating the mechanisms underlying mood alterations and other BPSDs in AD may reveal novel avenues for progress in AD therapy. Purinergic signaling is implicated in the pathophysiology of several CNS disorders, such as AD, depression and sleep disorders. Here, we review recent findings indicating that purinergic receptors, mainly the A

Background: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by progressive cognitive decline. Considerable evidence supports an important role of amyloid-β oligomers (AβOs) in the pathogenesis of AD, including the induction of aberrant glial activation and memory impairment. Objective: We have investigated the protective actions of a nutritional formulation, denoted AZ formulation, on glial activation and memory deficits induced by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Methods: Two-month-old male mice were treated orally with AZ formulation or isocaloric placebo for 30 consecutive days. Microglial and astrocytic activation were analyzed by immunohistochemistry in the hippocampus 10 days after i.c.v. infusion of AβOs (n = 5 mice per experimental condition). Memory loss was assessed by the novel object recognition (NOR) test (n = 6–10 mice per experimental condition). Results: Oral treatment with the AZ formulation prevented hippocampal microglial and astrocytic activation induced by i.c.v. infusion of AβOs. The AZ formulation further protected mice from AβO-induced memory impairment. Conclusion: Results suggest that administration of the AZ formulation may comprise a promising preventative and non-pharmacological strategy to reduce brain inflammation and attenuate memory impairment in AD.

Sepsis survivors show long-term impairments, including alterations in memory and executive function. Evidence suggests that systemic inflammation contributes to the progression of Alzheimeŕs disease (AD), but the mechanisms involved in this process are still unclear. Boosted (trained) and diminished (tolerant) innate immune memory has been described in peripheral immune cells after sepsis. However, the occurrence of long-term innate immune memory in the post-septic brain is fully unexplored. Here, we demonstrate that sepsis causes long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to Aβ oligomers (AβO), central neurotoxins found in AD. Hippocampal microglia from sepsis-surviving mice shift to an amoeboid/phagocytic morphological profile when exposed to low amounts of AβO, and this event was accompanied by the upregulation of several pro-inflammatory proteins (IL-1β, IL-6, INF-γ and P2X7 receptor) in the mouse hippocampus, suggesting that a trained innate immune memory occurs in the brain after sepsis. Brain exposure to low amounts of AβO increased microglial phagocytic ability against hippocampal synapses. Pharmacological blockage of brain phagocytic cells or microglial depletion, using minocycline and colony stimulating factor 1 receptor inhibitor (PLX3397), respectively, prevents cognitive dysfunction induced by AβO in sepsis-surviving mice. Altogether, our findings suggest that sepsis induces a long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to AβO-induced neurotoxicity and cognitive impairment.

International audience; No abstract available

Introduction Dementia has been associated with COVID-19 prevalence, but whether this reflects higher infection, older age of patients, or disease severity remains unclear Methods We investigated a cohort of 12,863 UK Biobank community-dwelling individuals > 65 years old (1814 individuals >= 80 years old) tested for COVID-19 Individuals were stratified by age to account for age as a confounder Risk factors were analyzed for COVID-19-positive diagnosis, hospitalization, and death Results All-cause dementia, Alzheimer's disease (AD), and Parkinson's disease (PD) were associated with COVID-19-positive diagnosis, and all-cause dementia and AD remained associated in individuals >= 80 years old All-cause dementia, AD, or PD were not risk factors for overall hospitalization, but increased the risk of hospitalization of COVID-19 patients All-cause dementia and AD increased the risk of COVID-19-related death, and all-cause dementia was uniquely associated with increased death in >= 80-year-old patients Discussion All-cause dementia and AD are age-independent risk factors for disease severity and death in COVID-19 (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Alzheimer’s disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) has been implicated in synapse failure and memory impairment in Alzheimer’s disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets AβOs, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by AβOs in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-associated virus vector to drive neuronal expression of NUsc1 (AAV-NUsc1) within the brain. Transduction by AAV-NUsc1 induced NUsc1 expression and secretion in adult human brain slices, and inhibited AβO binding to neurons and AβO-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AβOs and, importantly, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer’s disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimer’s disease.

Alzheimer’s disease (AD) is the main cause of dementia in the elderly and is characterized by memory loss, social withdrawal and neurodegeneration, eventually leading to death. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. We investigated oxytocin production in mouse models of AD, and evaluated the therapeutic potential of intranasal oxytocin. We observed lower levels of hypothalamic oxytocin in wild-type mice following brain infusion of amyloid-β oligomers (AβOs), as well as in APP/PS1 AD model mice. Treatment of APP/PS1 mice with intranasal oxytocin reduced microglial activation and favored deposition of Aβ in dense core plaques, a potentially neuroprotective mechanism. Oxytocin further alleviated social and non-social memory impairments in APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF. Fil: Parra, Mario Alfredo. Universidad Autónoma del Caribe; Colombia Fil: Baez, Sandra. Universidad de los Andes; Colombia Fil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gonzalez Campo, Cecilia. Universidad de San Andrés; Argentina Fil: Santamaría García, Hernando. Pontificia Universidad Javeriana; Colombia Fil: Aprahamian, Ivan. No especifíca; Fil: Bertolucci, Paulo. Universidade Federal de Sao Paulo; Brasil Fil: Bustin, Julian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Camargos Bicalho, Maria Aparecida. Universidade Federal de Minas Gerais; Brasil Fil: Cano Gutierrez, Carlos. Hospital Universitario San Ignacio; Colombia Fil: Caramelli, Paulo. Universidade Federal de Minas Gerais; Brasil Fil: Chaves, Marcia L. F.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Perez Cogram, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina Fil: Beber, Bárbara Costa. Universidade Federal do Rio Grande do Sul; Brasil Fil: Court, Felipe A.. Universidad Mayor; Chile Fil: de Souza, Leonardo Cruz. Universidade Federal de Minas Gerais; Brasil Fil: Custodio, Nilton. Peruvian Institute of Neurosciences; Perú Fil: Damian, Andres. Universidad de la República; Uruguay Fil: de la Cruz, Myriam. University of California; Estados Unidos Fil: Diehl Rodriguez, Roberta. Universidade de Sao Paulo; Brasil Fil: Dozzi Brucki, Sonia Maria. Universidade de Sao Paulo; Brasil Fil: Fajersztajn, Lais. Universidade de Sao Paulo; Brasil Fil: Farías, Gonzalo A.. Universidad de Chile; Chile Fil: De Felice, Fernanda G.. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferrari, Raffaele. Colegio Universitario de Londres; Reino Unido Fil: Ferreira de Oliveira, Fabricio. Universidade de Sao Paulo; Brasil Fil: Ferreira, Sergio Teixeira. Universidade Federal do Rio de Janeiro; Brasil Fil: Ferretti, Ceres. Universidade de Sao Paulo; Brasil Fil: Figueredo Balthazar, Marcio Luiz. Universidade Estadual de Campinas; Brasil Fil: Ferreira Frota, Norberto Anizio. Universidade de Fortaleza; Brasil Fil: Fuentes, Patricio. No especifíca; Fil: García, Adolfo Martín. Universidad Nacional de Cuyo; Argentina. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Garcia, Patricia J.. Cayetano Heredia University; Perú Fil: de Gobbi Porto, Fábio Henrique. Universidade de Sao Paulo; Brasil Fil: Duque Peñailillo, Lissette. Ecuadorian Dementia Association; Ecuador Fil: Engler, Henry Willy. Universidad de la República; Uruguay Fil: Maier, Irene. Universidad de Chile; Chile Fil: Mata, Ignacio F.. University of Pittsburgh; Estados Unidos Fil: González Billault, Christian. Universidad de Chile; Chile Fil: Lopez, Oscar L.. University of Pittsburgh; Estados Unidos Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Nitrini, Ricardo. Universidade de Sao Paulo; Brasil Fil: Quiroz, Yakeel T.. Harvard Medical School; Estados Unidos Fil: Guerrero Barragan, Alejandra. Universidad de la Sabana; Colombia Fil: Huepe, David. Universidad Adolfo Ibañez; Chile Fil: Pio, Fabricio Joao. Hospital Governador Celso Ramos; Brasil Fil: Suemoto, Claudia Kimie. Universidade de Sao Paulo; Brasil Fil: Kochhann, Renata. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Kochen, Sara Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina Fil: Kumfor, Fiona. University of Western Sydney; Australia Fil: Lanata, Serggio. University of California; Estados Unidos Fil: Miller, Bruce. University of California; Estados Unidos Fil: Lessa Mansur, Leticia. Universidade de Sao Paulo; Brasil Fil: Lie Hosogi, Mirna. Universidade de Sao Paulo; Brasil Fil: Lillo, Patricia. Universidad de Chile; Chile Fil: Llibre Guerra, Jorge. University of California; Estados Unidos Fil: Lira, David. Peruvian Institute of Neurosciences; Perú Fil: Lopera, Francisco. Universidad de Antioquia; Colombia Fil: Comas, Adelina. No especifíca; Fil: Avila Funes, José Alberto. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; México Fil: Sosa, Ana Luisa. Instituto Nacional de Neurología y Neurocirugía; México Fil: Ramos, Claudia. University of California; Estados Unidos Fil: de Paula França Resende, Elisa. University of California; Estados Unidos Fil: Snyder, Heather M.. No especifíca; Fil: Tarnanas, Ioannis. University of California; Estados Unidos Fil: Yokoyama, Jenifer. University of California; Estados Unidos Fil: Llibre, Juan. Centro de Estudios de Alzheimer; Cuba Fil: Cardona Londoño, Juan Felipe. Universidad del Valle; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Possin, Kate. University of California; Estados Unidos Fil: Kosik, Kenneth. University of California; Estados Unidos Fil: Montesinos, Rosa. Peruvian Institute of Neurosciences; Perú Fil: Moguilner, Sebastian Gabriel. University of California; Estados Unidos Fil: Solis, Patricia Cristina Lourdes. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; Argentina. Universidad de Buenos Aires; Argentina Fil: de Lucena Ferretti Rebustini, Renata Eloah. Universidade de Sao Paulo; Brasil Fil: Ramirez, Jeronimo Martin. No especifíca; Fil: Matallana, Diana. Pontificia Universidad Javeriana; Colombia Fil: Mbakile Mahlanza, Lingani. University of California; Estados Unidos Fil: Mendonça Marques Ton, Alyne. Universidade Federal do Rio de Janeiro; Brasil Fil: Melo Tavares, Ronnielly. Centro Universitario de Belo Horizonte.; Brasil Fil: Miotto, Eliane C.. Universidade de Sao Paulo; Brasil Fil: Muniz-Terrera, Graciela. University of Edinburgh; Reino Unido Fil: MuñozN evárez, Luis Arnoldo. University of California; Estados Unidos Fil: Orozco, David. Universidad Nacional del Sur; Argentina Fil: Okada de Oliveira, Maira. University of California; Estados Unidos Fil: Piguet, Olivier. University of Western Sydney; Australia Fil: Pintado Caipa, Maritza. University of California; Estados Unidos Fil: Piña Escudero, Stefanie Danielle. University of California; Estados Unidos Fil: Porcello Schilling, Lucas. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Rodrigues Palmeira, André Luiz. Hospital Ernesto Dornelles; Brasil Fil: Sanches Yassuda, Mônica. Universidade de Sao Paulo; Brasil Fil: Santacruz Escudero, Jose Manuel. Pontificia Universidad Javeriana; Colombia Fil: Serafim, Rodrigo Bernardo. Universidade Federal do Rio de Janeiro; Brasil Fil: Smid, Jerusa. Universidade de Sao Paulo; Brasil Fil: Slachevsky, Andrea. Universidad de Chile; Chile Fil: Serrano, Cecilia Mariela. No especifíca; Fil: Soto Añari, Marcio. Universidad Católica San Pablo; Perú Fil: Takada, Leonel Tadao. Universidade de Sao Paulo; Brasil Fil: Tenenholz Grinberg, Lea. Universidade de Sao Paulo; Brasil Fil: Teixeira, Antonio Lucio. Universidade Federal de Minas Gerais; Brasil Fil: Tonidandel Barbosa, Maira. Universidade Federal de Minas Gerais; Brasil Fil: Trépel, Dominic. Trinity College; Estados Unidos Fil: Ibañez, Agustin Mariano. Universidad Autónoma del Caribe; Colombia. Universidad Adolfo Ibañez; Chile. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

International audience; Converging evidence indicates that neurotoxicity and memory impairment in Alzheimer's disease is induced by brain accumulation of soluble amyloid-β oligomers (AβOs). Physiological metals are poorly distributed and concentrated in the senile plaques typical of Alzheimer's disease, where they may be coordinated to the amyloid-β peptide (Aβ). Indeed, zinc and copper increase Aβ oligomerization and toxicity. Metal-protein attenuating compounds represent a class of agents proposed for Alzheimer's disease treatment, as they reduce abnormal interactions of metal ions with Aβ, inhibit Aβ oligomerization and prevent deleterious redox reactions in the brain. The present work investigates the protective action of an isoniazid-derived aroylhydrazone, INHHQ, on AβO-induced memory impairment. Systemic administration of a single dose of INHHQ (1 mg/kg) prevented both short-term and long-term memory impairment caused by AβOs in mice. In-vitro studies showed that INHHQ prevents Cu(Aβ)-catalyzed production of reactive oxygen species. Although the mechanism of protection by INHHQ is not yet fully understood at a molecular level, the results reported herein certainly point to the value of aroylhydrazones as promising neuroprotective agents in Alzheimer's disease and related disorders.

Amyloid-β (Aβ) dysmetabolism is tightly associated with pathological processes in Alzheimer's disease (AD). Currently, it is thought that, in addition to Aβ fibrils that give rise to plaque formation, Aβ aggregates into non-fibrillar soluble oligomers (AβOs). Soluble AβOs have been extensively studied for their synaptotoxic and neurotoxic properties. In this review, we discuss physicochemical properties of AβOs and their impact on different brain cell types in AD. Additionally, we summarize three decades of studies with AβOs, providing a compelling bulk of evidence regarding cell-specific mechanisms of toxicity. Cellular models may lead us to a deeper understanding of the detrimental effects of AβOs in neurons and glial cells, putatively shedding light on the development of innovative therapies for AD.

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer’s disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes infndc5expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreasedfndc5expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreasedfndc5expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increasedfndc5expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in alteredfndc5expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increasedfndc5gene expression in the mouse frontal cortex. Results indicate a region-specific modulation offndc5in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortexfndc5expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction infndc5mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.

Acute neurological alterations have been associated with SARS-CoV-2 infection. Additionally, it is becoming clear that coronavirus disease 2019 (COVID-19) survivors may experience long-term neurological abnormalities, including cognitive deficits and mood alterations. The mechanisms underlying acute and long-term impacts of COVID-19 in the brain are being actively investigated. Due to the heterogeneous manifestations of neurological outcomes, it is possible that different mechanisms operate following SARS-CoV-2 infection, which may include direct brain infection by SARS-CoV-2, mechanisms resulting from hyperinflammatory systemic disease, or a combination of both. Inflammation is a core feature of COVID-19, and both central and systemic inflammation are known to lead to acute and persistent neurological alterations in other diseases. Here, we review evidence indicating that COVID-19 is associated with neuroinflammation, along with blood-brain barrier dysfunction. Similar neuroinflammatory signatures have been associated with Alzheimer's disease and major depressive disorder. Current evidence demonstrates that patients with pre-existing cognitive and neuropsychiatric deficits show worse outcomes upon infection by SARS-CoV-2 and, conversely, COVID-19 survivors may be at increased risk of developing dementia and mood disorders. Considering the high prevalence of COVID-19 patients that recovered from infection in the world and the alarming projections for the prevalence of dementia and depression, investigation of possible molecular similarities between those diseases may shed light on mechanisms leading to long-term neurological abnormalities in COVID-19 survivors.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Emerging evidence indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can cause neurological complications. We provide a brief overview of these recent observations and discuss some of their possible implications. In particular, given the global dimension of the current pandemic, we highlight the need to consider the possible long-term impact of COVID-19, potentially including neurological and neurodegenerative disorders.

BackgroundMesenchymal stem cells (MSCs) have been explored as promising tools for treatment of several neurological and neurodegenerative diseases. MSCs release abundant extracellular vesicles (EVs) containing a variety of biomolecules, including mRNAs, miRNAs, and proteins. We hypothesized that EVs derived from human Wharton’s jelly would act as mediators of the communication between hMSCs and neurons and could protect hippocampal neurons from damage induced by Alzheimer’s disease-linked amyloid beta oligomers (AβOs).MethodsWe isolated and characterized EVs released by human Wharton’s jelly mesenchymal stem cells (hMSC-EVs). The neuroprotective action of hMSC-EVs was investigated in primary hippocampal cultures exposed to AβOs.ResultshMSC-EVs were internalized by hippocampal cells in culture, and this was enhanced in the presence of AβOs in the medium. hMSC-EVs protected hippocampal neurons from oxidative stress and synapse damage induced by AβOs. Neuroprotection by hMSC-EVs was mediated by catalase and was abolished in the presence of the catalase inhibitor, aminotriazole.ConclusionshMSC-EVs protected hippocampal neurons from damage induced by AβOs, and this was related to the transfer of enzymatically active catalase contained in EVs. Results suggest that hMSC-EVs should be further explored as a cell-free therapeutic approach to prevent neuronal damage in Alzheimer’s disease.

Neurological complications affecting the central nervous system have been reported in adult patients infected by Zika virus (ZIKV) but the underlying mechanisms remain unknown. Here, we report that ZIKV replicates in human and mouse adult brain tissue, targeting mature neurons. ZIKV preferentially targets memory-related brain regions, inhibits hippocampal long-term potentiation and induces memory impairment in adult mice. TNF-α upregulation, microgliosis and upregulation of complement system proteins, C1q and C3, are induced by ZIKV infection. Microglia are found to engulf hippocampal presynaptic terminals during acute infection. Neutralization of TNF-α signaling, blockage of microglial activation or of C1q/C3 prevent synapse and memory impairment in ZIKV-infected mice. Results suggest that ZIKV induces synapse and memory dysfunction via aberrant activation of TNF-α, microglia and complement. Our findings establish a mechanism by which ZIKV affects the adult brain, and point to the need of evaluating cognitive deficits as a potential comorbidity in ZIKV-infected adults., Here, using ex-vivo human adult cortical tissue and a mouse model, the authors investigate the functional consequences of Zika virus (ZIKV) infection in the adult brain, and show that ZIKV causes synapse damage and altered brain function that impacts cognition via activation of innate and inflammatory factors.

Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment).

Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusions: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Although the brain was once considered an insulin-independent organ, insulin signalling is now recognised as being central to neuronal health and to the function of synapses and brain circuits. Defective brain insulin signalling, as well as related signalling by insulin-like growth factor 1 (IGF-1), is associated with neurological disorders, including Alzheimer's disease, suggesting that cognitive impairment could be related to a state of brain insulin resistance. Here, I briefly review key epidemiological/clinical evidence of the association between diabetes, cognitive decline and AD, as well as findings of reduced components of insulin signalling in AD brains, which led to the initial suggestion that AD could be a type of brain diabetes. Particular attention is given to recent studies illuminating mechanisms leading to neuronal insulin resistance as a key driver of cognitive impairment in AD. Evidence of impaired IGF-1 signalling in AD is also examined. Finally, we discuss potentials and possible limitations of recent and on-going therapeutic approaches based on our increased understanding of the roles of brain signalling by insulin, IGF-1 and glucagon-like peptide 1 in AD.

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer's disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

Amyloid-β (Aβ) dysmetabolism is thought to be the main trigger for neurodegenerative events in Alzheimer's disease (AD). In particular, soluble Aβ oligomers (AβOs) are proposed as key mediators of synaptic and cognitive dysfunction in AD. Over the past few decades, AβOs prepared from synthetic Aβ have been widely applied in vitro and in vivo, the so-called chemical models of AD, uncovering their multiple neurotoxic mechanisms. However, the lack of a reliable quality control (QC) for synthetic AβOs may reflect poor experimental reproducibility. In keeping with this, we optimized and validated a rapid and reproducible SECHPLC method using fluorescence detection for the QC of synthetic AβOs. Our analytical method offers an unprecedent alternative to improve the reproducibility of AD chemical models.

Neuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number of neurodegenerative disorders, including Alzheimer’s disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2α-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR with the small molecule compound ISRIB (ISR Inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2α-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD.

Made available in DSpace on 2020-12-10T20:08:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-04-21 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) Institutos Nacionais de Pesquisa - Instituto Nacional de Neurociencia Translacional Institutos Nacionais de Pesquisa - Inovacao em Medicamentos e Identificacao de Novos Alvos Terapeuticos Modulation of brain activity is one of the main mechanisms capable of demonstrating the synchronization dynamics of neural oscillations. In epilepsy, modulation is a key concept since seizures essentially result from neural hypersynchronization and hyperexcitability. In this study, we have introduced a time-dependent index based on the Kullback-Leibler divergence to quantify the effects of phase and frequency modulations of neural oscillations in neonatal mice exhibiting epileptiform activity induced by Zika virus (ZIKV) infection. Through this index, we demonstrate that fast oscillations (gamma and beta 2) are the more susceptible modulated rhythms in terms of phase, during seizures, whereas slow waves (delta and theta) mainly undergo changes in frequency. The index also allowed detection of specific patterns associated with the interdependent modulation of phase and frequency in neural activity. Furthermore, by comparing ZIKV modulations with the general computational model Epileptors, we verify different signatures related to the brain rhythms modulation in phase and frequency. These findings instigate new studies on the effects of ZIKV infection on neuronal networks from electrophysiological activities, and how different mechanisms can trigger epilepsy. Fed Univ Sao Paulo UNIFESP, Paulista Sch Med, Dept Neurol & Neurosurg, Sao Paulo, Brazil Fed Univ Rio De Janeiro UFRJ, Sch Pharm, BR-21944590 Rio De Janeiro, RJ, Brazil Sao Paulo State Univ, Dept Mech Engn, BR-15385000 Ilha Solteira, SP, Brazil Sao Paulo State Univ, Dept Math, BR-15385000 Ilha Solteira, SP, Brazil Fed Univ Rio de Janeiro UFRJ, Inst Microbiol Paulo de Goes, BR-21944590 Rio De Janeiro, RJ, Brazil Fed Univ Rio de Janeiro UFRJ, Inst Med Biochem Leopoldo de Meis, BR-21944590 Rio De Janeiro, RJ, Brazil Fed Univ Rio de Janeiro UFRJ, Inst Biophys Carlos Chagas Filho, BR-21944590 Rio De Janeiro, RJ, Brazil Fed Univ Sao Paulo UNIFESP, Inst Sci & Technol, Nucleus Neuroengn & Computat, Sao Paulo, Brazil Sao Paulo State Univ, Dept Mech Engn, BR-15385000 Ilha Solteira, SP, Brazil Sao Paulo State Univ, Dept Math, BR-15385000 Ilha Solteira, SP, Brazil CAPES: 001 CAPES: AUXPE: 0561/2018 CNPq: 442563/2016-7