Dlgap2 as a Regulator of Alzheimer's Disease Related Cognitive Declines Via Synaptic Modifications - 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.
