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Background: A brain healthy lifestyle, consisting of good cardiometabolic health and being cognitively and socially active in midlife, is associated with a lower risk of cognitive decline years later. However, it is unclear whether lifestyle changes over time also affect the risk for mild cognitive impairment (MCI)/dementia, and rate of cognitive decline., Objectives: To investigate if lifestyle changes over time are associated with incident MCI/dementia risk and rate of cognitive decline., Design: Population-based prospective cohort study SETTING: Personality and Total Health (PATH) Through Life Study cohort (Australia)., Participants: 4,777 participants (50.4% women), recruited between 2000 and 2002, who were 40-44 and 60-64 years old at baseline, without a prevalent dementia diagnosis. Participants had to have cognitive outcome measures available after baseline., Measurements: Various measurements (neurocognitive assessment, blood pressure) and survey responses (demographics, cognitive, social, and physical activity, smoking, alcohol consumption, body height and weight, depression, and previous diagnoses) were collected approximately every four years. A brain-healthy lifestyle was operationalized via two well-validated modifiable dementia risk scores, the LIfestyle for BRAin health (LIBRA) score and the modifiable part of the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI mod ). Their change over time was estimated using latent growth curve modelling, and their association with cognition and incidence of MCI/dementia was investigated using parallel process modelling and Cox regression analysis., Results: Within those aged 60-64 years at baseline (n=2,409), 211 cases of incident MCI/dementia were recorded over a median follow-up time of 12.2 years. On average, individuals' LIBRA and ANU-ADRI mod increased (i.e., worsened) over time, but individuals whose scores increased one standard deviation (SD) less had a 19.0-24.6% lower risk for MCI/dementia (hazard ratio (95% confidence interval): LIBRA change over time =0.754 (0.664-0.857), ANU-ADRI mod, change over time =0.810 (0.71-0.915)), while controlling for the risk score at baseline and multiple potential confounders. Various associations between dementia risk score trajectories and cognitive performance trajectories were observed., Conclusions: Efforts to maintain a brain healthy lifestyle could reduce the risk for MCI or dementia, and slow cognitive decline., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors., Methods: Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel's C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer-Lemeshow goodness of fit test along calibration plots., Results: Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65)., Conclusions: The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures., (© 2024. The Author(s).)

Introduction: Few studies have explored dementia risk according to sex and gender including for transgender and non-binary adults. This study evaluated dementia risk factors and risk scores among cisgender, transgender, and non-binary adults., Methods: Observational data were drawn from the 2019 Behavioral Risk Factor Surveillance System. A matched-cohort approach was used to develop sex (male, female) and gender identity cohorts (cisgender men, cisgender women, transgender men, transgender women, and non-binary adults) for comparison. Dementia risk scores were calculated using established mid-life and late-life risk score algorithms., Results: Males had higher overall mid-life dementia risk, and lower late-life Alzheimer's disease risk compared to females. Transgender men, transgender women, and non-binary adults had higher overall late-life risk compared to both cisgender men and women., Discussion: Future research is needed to build the evidence base for specific risk factors that may be contributing to higher overall risk among understudied and underserved gender groups., Highlights: Using data from the 2019 Behavioral Risk Factor Surveillance System, this matched-cohort study found that those assigned female at birth had lower overall mid-life dementia risk and higher overall late-life Alzheimer's disease (AD) risk compared to those assigned male at birth. Transgender men, transgender women, and non-binary adults all showed higher overall late-life AD risk compared to cisgender men and cisgender women. Between-group differences were found in the incidence of specific risk and protective factors for dementia and AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Current efforts to reduce dementia focus on prevention and risk reduction by targeting modifiable risk factors. As dementia and cardiometabolic non-communicable diseases (NCDs) share risk factors, a single risk-estimating tool for dementia and multiple NCDs could be cost-effective and facilitate concurrent assessments as compared with a conventional single approach. The aim of this study is to develop and validate a new risk tool that estimates an individual's risk of developing dementia and other NCDs including diabetes mellitus, stroke and myocardial infarction. Once validated, it could be used by the public and general practitioners., Methods and Analysis: Ten high-quality cohort studies from multiple countries were identified, which met eligibility criteria, including large representative samples, long-term follow-up, data on clinical diagnoses of dementia and NCDs, recognised modifiable risk factors for the four NCDs and mortality data. Pooled harmonised data from the cohorts will be used, with 65% randomly allocated for development of the predictive model and 35% for testing. Predictors include sociodemographic characteristics, general health risk factors and lifestyle/behavioural risk factors. A subdistribution hazard model will assess the risk factors' contribution to the outcome, adjusting for competing mortality risks. Point-based scoring algorithms will be built using predictor weights, internally validated and the discriminative ability and calibration of the model will be assessed for the outcomes. Sensitivity analyses will include recalculating risk scores using logistic regression., Ethics and Dissemination: Ethics approval is provided by the University of New South Wales Human Research Ethics Committee (UNSW HREC; protocol numbers HC200515, HC3413). All data are deidentified and securely stored on servers at Neuroscience Research Australia. Study findings will be presented at conferences and published in peer-reviewed journals. The tool will be accessible as a public health resource. Knowledge translation and implementation work will explore strategies to apply the tool in clinical practice., Competing Interests: Competing interests: JES has received honoraria for scientific advisory, lectures, and clinical research from Pfizer; Roche; Zuellig Pharma; Astra Zeneca; Sanofi; Novo Nordisk; MSD; Eli Lilly; Abbott; Mylan; Boehringer Ingelheim. CSA has received grants from Takeda, Penumbra and Credit Pharma awarded to his institution outside of this work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Importance: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited., Objective: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI)., Design, Setting, and Participants: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023., Main Outcomes and Measures: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk., Results: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar., Conclusions and Relevance: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

Background: Dementia risk reduction is a public health priority and general practitioners (GPs) play a pivotal role in preventative healthcare. Therefore, risk assessment tools should be designed with GPs' preferences and perspectives in mind., Objective: The LEAD! GP project aimed to investigate Australian GPs' preferences and perspectives relating to design, use and implementation of a new risk assessment tool that simultaneously calculates risk for four outcomes- dementia, diabetes mellitus, myocardial infarct, and stroke., Methods: A mixed methods study using semi-structured interviews of a diverse group of 30 Australian GPs was conducted. Interview transcripts were analyzed thematically. Demographics and questions that elicited categorical answers were analyzed descriptively., Results: Overall, GPs felt that preventative healthcare was important with some finding it rewarding, and others finding it difficult. GPs currently use many risk assessment tools. GPs' perception of the usefulness and negatives/barriers of tools related to clinical practice applicability, patient engagement, and practical aspects. The largest barrier was lack of time. GPs responded positively to the concept of a four-in-one tool and preferred it to be relatively short, supported by practice nurses and some patient involvement, linked to education resources, available in different formats, and integrated into practice software., Conclusion: GPs recognize the importance of preventative healthcare and the potential benefit of a new tool that simultaneously predicts risk for those four outcomes. Findings provide important guidance to inform the final development and piloting of this tool with potential to improve efficiency and practical integration of preventative healthcare for dementia risk reduction.

Introduction: We aimed to develop a comprehensive risk assessment tool for Alzheimer's disease (AD), vascular dementia (VaD), and any dementia, that will be applicable in high and low resource settings., Method: Risk factors which can easily be assessed in most settings, and their effect sizes, were identified from an umbrella review, or estimated using meta-analysis where new data were available., Results: Seventeen risk/protective factors met criteria for the algorithm to estimate risk for any dementia including age, sex, education, hypertension, midlife obesity, midlife high cholesterol, diabetes, insufficient physical activity, depression, traumatic brain injury, atrial fibrillation, smoking, social engagement, cognitive engagement, fish consumption (diet), stroke, and insomnia. A version for AD excluded atrial fibrillation and insomnia due to insufficient evidence and included pesticide exposure. There was insufficient evidence for a VaD risk score., Discussion: Validation of the tool on external datasets is planned. The assessment tool will assist with implementing risk reduction guidelines., Competing Interests: K.J.A. received a speaker honorarium from Nutricia in 2021. There are no other conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Anxiety disorders are highly prevalent and cause significant distress, disability, and cost. Medication adverse effects and interactions increase in mid-life and late-life, highlighting the need for effective non-pharmacological interventions., Objectives: We aimed to evaluate the extent of evidence supporting exercise interventions for anxiety and subthreshold anxiety disorders in mid-life and late-life., Design: Systematic review., Data Sources and Methods: We searched MEDLINE, PsycINFO, Embase, Emcare, Ovid Nursing, CINAHL Plus, Cochrane Library, Health Collection, Humanities & Social Sciences Collection, and https://clinicaltrials.gov databases for trials published January 1994-May 2019. Randomised controlled trials of exercise interventions involving aerobic exercise or resistance training for adults aged 40 years and above with anxiety or subthreshold anxiety disorders in residential or health settings were identified. The primary outcome was change in anxiety. We excluded trials including participants aged below 40 years, participants with diagnosis of separation anxiety, selective mutism, obsessive-compulsive disorder, acute stress disorder and post-traumatic stress disorder, and head-to-head comparisons of interventions. Trial quality was assessed using the Cochrane Risk of Bias Tool and evidence synthesised in narrative form., Results: Four trials totalling 132 participants met inclusion criteria, although some had methodological limitations. Interventions included a home-based resistance training intervention, supervised group-based aerobic intervention, Tai Chi intervention, and supervised group-based aerobic and strength intervention. Three trials included late-life participants and the fourth mid-life. Three trials demonstrated greater reductions in anxiety in the intervention group compared with control. The fourth trial showed pre-post reductions in anxiety in both groups, with between-group difference not reaching statistical significance., Conclusion: There is limited supportive evidence suggesting that exercise interventions have potential to be effective, feasible and safe non-pharmacological interventions for anxiety and subthreshold anxiety disorders in mid-life and late-life. The heterogeneity, limited number and high risk of bias of some trials meant that we were not able to conduct a meta-analysis. Tailoring of interventions may improve uptake and reduce dropout. The paucity of research in this area with only four included trials demonstrates the urgent need for future and larger trials to provide proof of concept, data about effective types and doses of exercise interventions, and guidance to community, clinical, and public health services., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Dementia prevention is a global health priority. In 2019, the World Health Organisation published its first evidence-based guidelines on dementia risk reduction. We are now at the stage where we need effective tools and resources to assess dementia risk and implement these guidelines into policy and practice. In this paper we review dementia risk scores as a means to facilitate this process. Specifically, we (a) discuss the rationale for dementia risk assessment, (b) outline some conceptual and methodological issues to consider when reviewing risk scores, (c) evaluate some dementia risk scores that are currently in use, and (d) provide some comments about future directions. A dementia risk score is a weighted composite of risk factors that reflects the likelihood of an individual developing dementia. In general, dementia risks scores have a wide range of implementations and benefits including providing early identification of individuals at high risk, improving risk perception for patients and physicians, and helping health professionals recommend targeted interventions to improve lifestyle habits to decrease dementia risk. A number of risk scores for dementia have been published, and some are widely used in research and clinical trials e.g., CAIDE, ANU-ADRI, and LIBRA. However, there are some methodological concerns and limitations associated with the use of these risk scores and more research is needed to increase their effectiveness and applicability. Overall, we conclude that, while further refinement of risk scores is underway, there is adequate evidence to use these assessments to implement guidelines on dementia risk reduction., Competing Interests: KA is an advisor to Staying Sharp. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Anstey, Zheng, Peters, Kootar, Barbera, Stephen, Dua, Chowdhary, Solomon and Kivipelto.)

Background: Findings on the associations between anxiety and cognitive decline are mixed and often confounded., Objective: We studied whether anxiety symptoms were associated with the risk of cognitive decline after adequate adjustment of confounding factors., Methods: Our study consists of 2,551 community-dwelling older adults recruited between the ages of 60-64 years and followed up for 12 years in the PATH Through Life cohort study. Anxiety symptoms were measured using the Goldberg Anxiety Scale (GAS; range 0-9). General cognitive function, episodic memory, working memory, verbal intelligence, processing speed, and psychomotor speed were measured. Multilevel analyses were carried out to investigate the association between anxiety symptoms and cognitive decline over 12 years, taking into account confounding variables., Results: We did not find a significant association between baseline anxiety symptoms and cognitive decline over 12 years. Although some associations between anxiety symptoms with psychomotor speed (β= -0.04, 99% CI: -0.08, 0.00) and processing speed (β= -0.27, 99% CI: -0.48, -0.07) were found, these were attenuated after adjusting for depression. We also did not find an association between cumulative anxiety and decline in cognitive performance., Conclusion: In this sample of cognitively healthy men and women aged 60 years and above, anxiety symptoms were not associated with the risk of cognitive decline. Long follow-up study time, appropriate selection of confounding factors, and estimating the effect of cumulative anxiety are important to establish the association between anxiety and cognitive symptoms.

Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.

Purpose: The purpose of this review is to provide an overview of established risk factors for all-type dementia and results of interventions on dementia modifiable risk factors, all with relevance to aging people living with HIV (PLHIV)., Methods: Narrative literature review., Results: Our review identifies a high prevalence of risk factors for dementia in the global HIV population that is entering dementia age range (60 +), in relation to both traditional and HIV-specific risk factors. This includes age (HIV-related premature aging and possibly HIV-related accelerated brain aging and cerebrovascular injury), HIV-related and non-HIV-related cardiovascular diseases burden with related-vascular brain damage, HIV-associated neurocognitive disorders, high mental health burden, low educational/socio-economic status, historical immune compromise, and persistent immune activation with consequent augmented immune senescence. Our review highlights that the results of interventions on all-type dementia modifiable factors show discrepancies between positive observational study results and inconclusive clinical trials. The main reasons for such discrepancies relate to the preventative framework that complex interventions' trials have difficulty to emulate and the suboptimal measurement of cognitive change. Multi-domain intervention trials are now advocated to concomitantly tackle complex age-related comorbid profiles., Conclusions: The burden of dementia risk in aging PLHIV is higher than that in the general population, particularly in the most vulnerable clusters. Epidemiological studies are urgently needed to provide accurate estimates. Lessons from interventions trials in all-type dementia on modifiable factors need to be carefully considered for enhancing trials' potential in aging PLHIV. A comprehensive and preventative neurogeriatric healthcare response linked with HIV communities and dementia associations should be urgently put in place., (© 2019. European Geriatric Medicine Society.)

Amyloid-β is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-β (Aβο) is now believed to represent the main Amyloid-β species affecting synapse function. Yet, the exact molecular mechanism by which Aβο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aβο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aβ and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aβo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aβo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aβo-mediated LTP impairment, but not Aβo-mediated LTD induction. The necessity of neuronal GRs for Aβo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aβ activities at excitatory synapses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Fellutamide B is reported to have cytotoxic and proteasome inhibitory activity. Interestingly, fellutamide B and its simplified analogues have also been observed for the neurotrophic activity by stimulating the synthesis and secretion of neurotrophins. Owing to the interesting structural and potent neurotrophic role of fellutamide B (a lipopeptide aldehyde), we have assessed the synthetic path intermediates (compounds A-D) of fellutamide B for their neuroactive potential (in vitro and in vivo). We have observed few compounds (comp #A-D) to have potential neurite outgrowth activity in Neuro2a cells with no observable negative effect on the cell viability. In addition, most compounds (comp #A, C, and D) have shown neurogenic activity ex vivo in hippocampal neurosphere culture, with increased acetyl H3 and acetyl H4 induction ability (comp #C). Furthermore, the intermediate product comp #C has shown anxiolytic and antidepressant-like activity in novel tank test and social interaction test, in the chronic unpredictable stress model of zebrafish mood disorder, inducing BDNF gene expression in the telencephalon region of the fish brain. Our results thus demonstrate that the fellutamide B synthetic path intermediates have potential neurotrophic, neurogenic, and mood-elevating effects and thus good prospect to be developed as potential therapeutics to treat psychiatric disorders., Competing Interests: The authors declare no competing financial interest.

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds.

The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.