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Principal Investigator: Andrew Ouellette
Organization: JACKSON LABORATORY
Fiscal Year: 2024
Award: $34,077
Funding agency: National Institute on Aging
PROJECT SUMMARY
To date, there is a significant knowledge gap surrounding the genetic and neuronal mechanisms that regulate
cognitive resilience to Alzheimer’s Disease (AD). Without a better understanding of these mechanisms,
developing therapeutics to enhance cognitive longevity in the face of AD will remain limited. Our recently
published work, which utilized human-mouse cross-species analysis, identified the post-synaptic gene Dlgap2
(Discs large associated protein 2) as a potential mediator of age- and AD-related cognitive decline through
changes to dendritic spine morphology, which concurs with other previous work investigating spines as a
mediator of AD-related cognitive resilience. My long-term goal for this work is to determine if Dlgap2 is a
genuine modifier of AD-related cognitive decline, and to build a better understanding of the role of Dlgap2 in
synaptic dysfunction during the progression of AD. The novel approach that I am employing is to modulate
Dlgap2 expression in hippocampal neurons of mice that model AD pathogenesis. Using a newly designed
Adeno-Associated Virus (AAV) carrying Dlgap2 with and neuron specific promotor, I will overexpress Dlgap2 in
the CA1 of AD mice. To date this is the first work to investigate the role of Dlgap2 in AD-related cognitive
decline. I hypothesize that increasing expression of Dlgap2 in hippocampal pyramidal neurons will enhance
synaptic and dendritic spine remodeling in CA1 and, ultimately, promote cognitive resilience to causal
mutations in our susceptible AD mouse model. I will test this hypothesis by evaluating the impact of changes in
Dlgap2 expression on cognitive aging on 3 different biological scales. 1) I will measure cognitive outcomes in
the hippocampal-dependent domains of working, short-term and long-term memory of young (6mo) and aged
(14mo) AD mice that overexpress Dlgap2 across both sexes. 2) In the same mice, I will determine if
overexpression of Dlgap2 in CA1 neurons results in an increase in EPSP spike coupling and/or Long-term
potentiation by using ex vivo whole-cell current-clamp recordings. These recordings will inform me if
overexpression of Dlgap2 in AD reinforces synaptic plasticity via modifications to interactions between
NMDAr/AMPAr and the postsynaptic density. 3) To investigate the effect of Dlgap2 on synaptic structure, I will
image dendritic spine morphology, a modifier of AD-related cognitive decline, of CA1 neurons that overexpress
Dlgap2. The work proposed here will help facilitate my training goals to acquire new skills and knowledge
including those pertaining to: new behavioral assays, electrophysiology, fluorescent microscopy, dendritic
spine imaging, and general wet lab skills. Additionally, this proposed work will greatly assist me in refining my
scientific communication skills, project management skills, and furthering my career development.
Terms: <AD dementia><AD model><AD pathology><AD related dementia><ADRD><Adeno-Associated Viruses><Age><Age Months><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease model><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease pathology><Alzheimer's disease related dementia><Alzheimer's pathology><Alzheimers Dementia><Ammon Horn><Antibodies><Behavioral Assay><Benign senescent forgetfulness><Biological><Care Givers><Caregivers><Cell Body><Cells><Clampings><Closure by clamp><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive aging><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Communication><Complementary DNA><Cornu Ammonis><Coupling><Data><Dendritic Spines><Dependoparvovirus><Dependovirus><Development><Disturbance in cognition><Dysfunction><EPSP><Electrophysiology><Electrophysiology (science)><Emotional><Excitatory Postsynaptic Potentials><Financial Hardship><Fostering><Functional disorder><Future><Gene Expression><Gene variant><Genes><Genetic><Goals><Health><Hemagglutinin><Heritability><Hippocampus><Human><Image><Immediate Memory><Impaired cognition><Individual Differences><Injections><Intervention><Intervention Strategies><Knowledge><Label><Leanness><Length of Life><Long-Term Potentiation><Longevity><Longterm Potentiation><Measures><Mediator><Mice><Mice Mammals><Microscopy><Modern Man><Modification><Morphology><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Outcome><Pathogenesis><Pathology><Pathway interactions><Patients><Physiopathology><Play><Population><Predisposition><Primary Senile Degenerative Dementia><Proteins><Publications><Publishing><Pyramidal neuron><Reporting><Research><Resolution><Risk Factors><Role><Scientific Publication><Series><Short-Term Memory><Shortterm Memory><Sight><Slice><Spinal Column><Spine><Staining method><Stains><Strepavidin><Streptavidin><Structure><Susceptibility><Synapses><Synaptic><Synaptic plasticity><System><Testing><Therapeutic><Thinness><Training><Vertebral column><Vision><Work><adeno associated virus group><age associated difference><age associated memory decline><age based difference><age dependent difference><age dependent variation><age difference><age related cognitive deficit><age related cognitive impairment><age related difference><age related memory dysfunction><age related variation><age specific difference><age-induced cognitive decline><age-related decline in cognition><age-related decline in cognitive function><aged><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><ages><aging population><allele variant><allelic variant><alzheimer model><backbone><biocytin><biologic><biotinyl L lysine><cDNA><career><career development><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cognitive defects><cognitive dysfunction><cognitive enhancement><cognitive loss><cognitive performance><cognitive task><cohort><conditioned fear><cost><dementia care><dendrite spine><density><design><designing><develop therapy><developmental><differ by age><difference across age><difference in age><discover genes><electrophysiological><experiment><experimental research><experimental study><experiments><fear conditioning><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><gene discovery><genetic variant><genomic variant><hippocampal><hippocampal pyramidal neuron><imaging><insight><intervention development><interventional strategy><long term memory><longterm memory><microscope imaging><microscopic imaging><microscopy imaging><mouse genetics><mouse model><murine model><neuronal><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><overexpress><overexpression><pathophysiology><pathway><population aging><post-synaptic nerves><post-synaptic neurons><postsynaptic><postsynaptic nerves><postsynaptic neurons><prevent><preventing><primary degenerative dementia><promoter><promotor><protective effect><protein expression><rate of change><resilience><resilient><resolutions><senile dementia of the Alzheimer type><sex><skills><social role><synapse><synapse function><synaptic function><therapeutic target><therapy development><touch panel><touch screen><touch screen panel><touchscreen><touchscreen panel><treatment development><variation by age><visual function><working memory>