Lrfn2 as a Novel Resilience Factor to Protect Against Alzheimer's Disease-Related Cortical Neurodegeneration

PROJECT SUMMARY/ABSTRACT The prevalence of Alzheimer's disease (AD) in the U.S. is expected to reach 12.7 million by 2050 if successful disease-modifying treatments are not identified. Without a better understanding of the genetic and neuronal mechanisms that drive AD progression, the development of new therapeutics to enhance cognitive longevity will remain limited. Alternatively, therapeutic strategies to promote cognitive resilience in the face of AD pathology are potentially effective methods to lessen the impact of AD. To identify gene candidates of resiliency I quantified neurodegeneration in the brains of the translationally-relevant AD-BXD mouse model of AD via immunohistochemistry (IHC) and used these imaging outcomes to complete genetic mapping. Using this approach, I identified Leucine Rich Repeat And Fibronectin Type III Domain Containing 2 (Lrfn2) as a potentially causal gene modifying AD-related cortical neurodegeneration. I hypothesize that Lrfn2 overexpression will rescue AD-related cortical neurodegeneration, synaptic dysfunction, and cognitive decline in the 5XFAD model of AD. I will test this hypothesis by developing a novel Lrfn2 overexpression transgenic mouse and evaluating the impact of changes in Lrfn2 expression on AD progression in three aims. Aim 1) I will measure the extent of cortical neurodegeneration in 5XFAD and nontransgenic mice with and without Lrfn2 overexpression in both male and female mice at 6 and 14 months of age. Results will indicate whether Lrfn2 is truly a causal modifier of cortical neurodegeneration. Aim 2a) To test the impact of Lrfn2 overexpression on synaptic plasticity I will perform ex vivo whole-cell current-clamp electrophysiology recordings in a separate cohort of mice. I will determine if overexpression of Lrfn2 in excitatory forebrain neurons rescues long-term potentiation deficits in 5XFAD animals. Aim 2b) To investigate the effect of Lrfn2 on synaptic structure, I will image dendritic spines to assess changes in spine morphology and density as a complementary measure of synapse stability and synaptic function associated with cognitive performance. Aim 3) To evaluate the role of Lrfn2 as a potential resilience factor to cognitive decline, I will execute mouse behavioral tasks measuring working, short-term, long-term, and working memory in the same mice used in Aim 1. To our knowledge, this will be the first study to evaluate Lrfn2 expression in the context of aging, AD, and cortical neurodegeneration. With the successful completion of these aims, I will achieve my long-term goal for this project by determining whether Lrfn2 modulation is a novel resilience therapeutic for AD treatment. The proposed work will facilitate the achievement of my training goals to acquire new skills and knowledge related to IHC, imaging, electrophysiology, dendritic spine characterization, behavioral assays, general wet-lab techniques, and professional development. Overall, the guidance of Drs. O'Connell and Kaczorowski; access to the outstanding core resources at The Jackson Laboratory; and the experience gained from this fellowship will be a significant step toward achieving my long-term career goal of becoming an independent academic scientist.