Biology subjects

Ouellette, A. R.

Publications and source records attributed to Ouellette, A. R..

5 recordsLinked to original sources

bioRxiv2025

Evaluation of hippocampal DLGAP2 overexpression on cognition, synaptic function, and dendritic spine structure in a translationally relevant AD mouse model

INTRODUCTIONDeveloping effective therapeutics for Alzheimers Disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age-related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model. METHODSDLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and nontransgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age. RESULTSDLGAP2 overexpression impaired synaptic plasticity and exacerbated AD-related memory deficits but had minimal effect on spine structure or intrinsic neuronal properties. DISCUSSIONWe highlight the complex role of DLGAP2 in AD pathology. Targeted interventions involving postsynaptic proteins must consider potential adverse effects on synaptic integrity and cognitive performance, particularly in the context of AD.

neuroscience↗

bioRxiv2025

A genetically-diverse mouse model reveals a complex gene-environment regulation of cognitive resilience and susceptibility to Alzheimer disease

Alzheimers disease (AD) has a complex etiology arising from largely unknown interactions between genetic and environmental (GxE) factors. Even in populations with causal familial Alzheimers disease mutations, there is variation in disease onset and progression, suggesting that clinical symptoms are modified by genetics and environment. Identification of such modifiers is critical, as mechanisms that promote resilience to high-risk AD mutations, unhealthy diet, or aging represent promising therapeutic targets for AD; global resilience factors that protect against multiple "hits" are among the highest priority for discovery. Both genetic and environmental protective factors in AD have been identified; however, GxE factors are incredibly difficult to study in human populations given complex genomes, poor self-reporting, limited data from underrepresented groups, and incompletely documented exposomes. Here, we (1) validate novel GxE tools using population of mouse strains that model the polygenic nature of human AD, (2) characterize individuals with cognitive resilience to high-risk genetic and dietary perturbations, (3) define and quantitate roles for genetics, sex, age, and diet, and (4) present data for the discovery of complex interactions that are nearly impossible to elucidate from humans or inbred mice. We found that a high-fat high-sugar (HFHS) diet is not universally damaging, as some strains showed an improved AD-related cognitive outcome when fed a HFHS diet, suggesting the need for personalized recommendations for dietary interventions in AD. Cognitive resilience to AD is polygenic; however, we found a locus on Chr 10 that was modestly associated with cognitive resilience to AD in females, and this association was strengthened by HFHS diet, pointing to an unexpected interaction between specific genetic loci and unhealthy diet in AD risk and resilience. This study is the first of its kind to explore characteristics of AD resilience and GxE interactions in a genetically diverse mouse model. We present a subset of strains that exemplify global cognitive resilience to be leveraged for deep mechanistic studies aimed toward development of resilience-based, personalized therapeutic interventions. HighlightsO_LIAD-BXD mouse models and data repository provide unprecedented tools for understanding individual differences arising from Gene x Environment factors in aging and AD. C_LIO_LIEvidence of global cognitive resilience to AD-relevant outcomes that is partially mediated by a resilience to aging and dietary risk factors. C_LIO_LICognitive resilience in AD-BXDs its polygenic nature, with a modest locus on Chr 10 whose association with resilience was amplified by a high-fat/high-sugar diet. C_LIO_LIThe genetic factors mediating resilience to AD in humans also predict cognitive resilience in AD-BXDs, suggesting robust, translatable global resilience factors. C_LI

neuroscience↗

bioRxiv2022

Conserved cell-type specific signature of resilience to Alzheimer's disease nominates role for excitatory cortical neurons

Alzheimers disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to "cognitive resilience" to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

neuroscience↗

bioRxiv2022

Life-long Dietary Restrictions have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls (AL) on Y-maze working memory and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging in the context of long-term memory. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with late-life long-term memory outcomes in mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with a neuronal monocarboxylate transporter encoded by Slc16a7 highlighted as novel target.

animal behavior and cognition↗

bioRxiv2019

Genetic background modifies CNS-mediated sensorimotor decline in the AD-BXD mouse population

Many patients with Alzheimers dementia also exhibit non-cognitive symptoms such as sensorimotor deficits, which can precede the onset of the hallmark cognitive deficits and significantly impact daily activities and an individuals ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and the relationship between sensorimotor and cognitive decline remain poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimers disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and their relationship to cognitive decline in these mice. We found that both age- and AD-related declines in coordination, balance, and vestibular function vary significantly across the panel, indicating that genetic background strongly influences the expressivity of the familial AD mutations used in the AD-BXD panel and their impact on motor function. Further, we found that motor decline is not associated withcognitive decline in either AD or aging, suggesting that sensorimotor deficits in AD occur - in part - through distinct mechanisms. Overall, the results presented here suggest that AD-related sensorimotor decline is strongly dependent on background genetics and is independent of dementia and cognitive deficits, suggesting that effective therapeutics for the entire spectrum of AD symptoms will likely require interventions targeting each distinct domain involved in the disease.

neuroscience↗