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.

PROJECT NARRATIVE Given that the current cost of Alzheimer’s Disease (AD) and dementia care is currently estimated at over $216 billion annually, treatments to delay or prevent AD-related cognitive decline would alleviate the immense financial burden and emotional toll currently facing patients and caregivers. However, without a better understanding of the genetic and neuronal mechanisms that underly AD, development of these treatments will not be possible. In the short term, I will determine if the gene Dlgap2 is a genuine mediator of AD-related cognitive decline and provide insight into dendritic spines as a therapeutic target of AD; in the long term, I will develop a better understanding of the synaptic mechanisms that contribute to AD and build a framework for future AD research.