# Disruption of neuronal signaling in Alzheimer’s disease and rescue by manipulating the innate immune receptor PirB

> **NIH NIH F32** · STANFORD UNIVERSITY · 2021 · $66,390

## Abstract

Project Summary
 Alzheimer’s disease (AD) is becoming more prevalent as our population ages and is characterized by
devastating memory loss and cognitive impairment. The pruning of neuronal synapses contributes to the
pathology of AD and is the best correlate of cognitive decline. Both oligomeric amyloid beta and
neuroinflammatory mechanisms can lead to synapse pruning in AD. While neurons and immune cells have
been shown to interact to drive pruning, the neuronal signaling downstream of this interaction is not well
understood. A major goal of this proposal is to determine neuronal signaling mechanisms driving synapse
pruning in mouse models of autosomal dominant AD at two ages and under varying conditions of both
aggregated amyloid beta and immune activation.
 Synapse pruning occurs naturally throughout development, and one hypothesis is that developmental
pruning mechanisms are dysregulated in AD. The Shatz lab made the surprising discovery that the innate
immune receptor, PirB, is expressed in neurons and has roles in synapse pruning over development. In
addition, PirB knockout in adult mice, either globally or in excitatory neurons alone, facilitates the rapid growth
of new synapses and re-opens critical period-like synaptic plasticity. PirB and its human homologue, LilrB2,
have both been shown to bind amyloid beta at high affinities, and germline global PirB knockout was shown to
protect against memory loss in the APP/PS1 mouse model of AD. While global germline knockout was
protective, in a therapeutic context, it is also important to determine the effect of PirB blockade in normally
reared adult mice at various stages of disease progression. In addition, while the Shatz lab identified a
signaling pathway linking PirB to synapse pruning, via the dephosphorylation of cofilin, no other signaling
pathways have been examined downstream of PirB in APP/PS1 mice.
 Here, I propose to test the hypothesis that neuronal gene expression is dysregulated in AD model mice
and can be restored with PirB KO, protecting against synapse loss. The experiments proposed should identify
new signaling pathways in neurons and at synapses downstream of PirB in AD model mice. I also propose to
block PirB in normally reared adult APP/PS1 mice to determine the therapeutic potential of PirB/LilrB2
blockade in AD. I focus on two stages of disease progression: 1) early, before plaque formation but when
synaptic and memory deficits have been reported, and 2) late, after plaque formation and heightened immune
activation. The central goal of this proposal is to use transcriptomic, biochemical, electrophysiological, and
behavioral techniques to elucidate signaling pathways downstream of PirB/LilrB2 in AD and demonstrate the
therapeutic potential of PirB blockade to ‘treat’ memory loss in APP/PS1 model mice. The long-term aim of this
research is to contribute to our understanding of the signaling mechanisms leading to synaptic pruning in
Alzheimer’s disease, as a first step tow...

## Key facts

- **NIH application ID:** 10231468
- **Project number:** 1F32AG069342-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Johanna Elizabeth Tomorsky
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231468

## Citation

> US National Institutes of Health, RePORTER application 10231468, Disruption of neuronal signaling in Alzheimer’s disease and rescue by manipulating the innate immune receptor PirB (1F32AG069342-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231468. Licensed CC0.

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