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

> **NIH NIH F31** · JACKSON LABORATORY · 2024 · $34,008

## Abstract

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 Kac...

## Key facts

- **NIH application ID:** 10903429
- **Project number:** 1F31AG087702-01
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Brianna Gurdon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,008
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903429

## Citation

> US National Institutes of Health, RePORTER application 10903429, Lrfn2 as a Novel Resilience Factor to Protect Against Alzheimer's Disease-Related Cortical Neurodegeneration (1F31AG087702-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10903429. Licensed CC0.

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