# Innate immune signaling at the synapse in development and pathological Alzheimer’s disease

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $409,395

## Abstract

Pathological Alzheimer’s disease (AD) is a major cause of dementia characterized by memory loss and
aggregation of insoluble beta amyloid plaques and tau tangles. Memories are stored at synapses, and it is
thought that an early driver of dementia may be synapse pruning occurring even before plaque deposition.
Extensive activity-dependent synaptic pruning also occurs during developmental critical periods when learning
and experience strengthen and stabilize actively used synapses, while others weaken and are pruned. In an
unbiased in vivo screen for genes regulated by neural activity during visual system development, my lab made
the unexpected discovery that specific Major Histocompatibility Class I (MHCI) molecules, famous for their
immune system roles, are expressed in neurons and at synapses. Next, we identified an innate immune MHCI
receptor expressed in neurons: PirB (Paired immunoglobulin-like receptor B). Functional studies in mice reveal
that the MHCI - PirB axis is required for synapse pruning during normal development. Genetic deletion of PirB
selectively in cortical pyramidal neurons, or pharmacologic blockade using a recombinant protein, rapidly
generates new spines and functional synapses even in adult cerebral cortex. In the APP/PS1 transgenic model
of autosomal dominant AD, mice lacking PirB are protected from memory loss at 9 months of age despite high
levels of beta amyloid. Remarkably, PirB is a receptor for soluble beta amyloid oligomers, with high affinity
saturable binding. This interaction hyperactivates cofilin signaling which drives actin depolymerization and
contributes to synapse pruning in the APP/PS1 AD mouse model. In human the LilrB (leukocyte immunoglobulin-
like receptor B) family of 5 related molecules are PirB homologs. Similar to PirB, LilrB1 and LilrB2 are known to
bind MHCI ligands, including HLA-A, B and C alleles, which are implicated in human GWAS and gene expression
studies of AD. We discovered that LilrB2 binds soluble beta amyloid oligomers with nanomolar affinity, and LilrB2
protein is expressed in human frontal lobe. A crystal structure of the interaction between beta amyloid and LilrB2
has been solved, confirming genuine structural interactions and pointing to novel drug targets for AD. A major
goal of this research is to test the hypothesis that innate immune signaling via MHCI-PirB/LilrB at the synapse is
disrupted by pathological oAbeta, and to connect observations in mice to human neurobiology by (1) studying
MHCI-PirB dependent signaling in neurons using RiboTag cell type- specific transcription profiling in AD model
mice, and (2) by identifying and studying the function of human homologs, the HLA Class I and LilrB receptor
families, in 3-dimensional forebrain organoids derived from human iPSCs, followed by validation in brain samples.
Results from these studies will build a bridge between mouse models of AD and human neurons. They should
also provide mechanistic information about how nervous and ...

## Key facts

- **NIH application ID:** 10582575
- **Project number:** 5R01AG065206-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Carla J Shatz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $409,395
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582575

## Citation

> US National Institutes of Health, RePORTER application 10582575, Innate immune signaling at the synapse in development and pathological Alzheimer’s disease (5R01AG065206-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10582575. Licensed CC0.

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