# MHCI and synapse loss in Alzheimer's disease models

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $423,982

## Abstract

SUMMARY
Despite decades of research, the cause of Alzheimer’s disease (AD) remains incompletely understood, current
treatments provide only minimal symptom relief, and there are no known cures. AD has consistently been
associated with aberrations in both synaptic and immune signaling pathways. However, a key gap in
knowledge is a lack of insight into how these two pathways cross communicate to initiate and sustain AD-
associated deficits. Work from our lab indicates that the classical major histocompatibility complex I (MHCI)
immune molecules are attractive candidates for linking immune signaling to synaptic deficits in AD. MHCI
molecules are expressed in the brain, specifically in neurons and at synapses, where they limit excitatory
synapse density and function. Recently, we found that surface MHCI (sMHCI) is upregulated in response to
amyloid-β (Aβ) and loss of MHCI prevents Aβ-induced synapse loss, thereby implicating this immune signaling
in AD pathology for the first time. MHCI may cause this synaptic degeneration through a novel interaction we
recently discovered between MHCI and neuroligin-1 (NL1), a synaptic adhesion molecule that modulates
synapse formation and plasticity. NL1 is downregulated by Aβ and this decrease is necessary for Aβ-induced
decreases in synapse density. NL1 has also been shown to be misregulated in humans with AD. Together, our
results suggest the hypothesis that MHCI acts through NL1 to cause synapse loss in AD and induce
hippocampal-dependent behavioral deficits. The central goal of this proposal is to determine the role for
MHCI signaling, and its interaction with the synaptic modulator NL1, in AD-associated synaptic and
behavioral phenotypes. To address this hypothesis, our lab has assembled tools from years of research
related to both MHCI and NL1, an innovative and novel long-term live imaging assay to study synapse
dynamics, and the expertise of new personnel in AD research and behavioral assays. We propose to explore
three aims: (i) determine if changes in sMHCI are required for Aβ-induced synapse loss in vitro, (ii) determine if
sMHCI requires NL1 signaling to cause Aβ-induced synapse loss in vitro, and (iii) determine if sMHCI is
required for AD-associated in vivo synaptic and behavioral phenotypes. If successful, this proposal will provide
valuable insight into the potential of MHCI as a therapeutic target for mitigating the synaptic and cognitive
phenotypes associated with AD.

## Key facts

- **NIH application ID:** 10372774
- **Project number:** 1R21AG071884-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** A Kimberley McAllister
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,982
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372774

## Citation

> US National Institutes of Health, RePORTER application 10372774, MHCI and synapse loss in Alzheimer's disease models (1R21AG071884-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10372774. Licensed CC0.

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