# The contribution of Ly6h to Alzheimers Disease

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $197,500

## Abstract

Abstract
 Although interest has focused on crucial roles for amyloid beta and phosphorylated tau in
pathogenesis of Alzheimer's disease (AD), an earlier and persistent hypothesis attributes
cognitive impairment to loss of cholinergic signaling. We recently demonstrated that all these
elements are linked by Ly6h, an endogenous inhibitor of Ca2+-permeable alpha7 nicotinic
acetylcholine receptors (nAChRs). We found that amyloid beta reduces Ly6h, resulting in
increased assembly of alpha7 nAChRs and thus a conversion of basal cholinergic to neurotoxic
signaling. Importantly, we also found that Ly6h levels in temporal cortex and cerebrospinal fluid
are inversely correlated with disease severity in AD patients. The present proposal seeks to
complement these findings with related data in an animal model of AD. In particular, we will
determine the degree to which lentiviral knockdown of Ly6h in the hippocampus exacerbates AD-
driven increases in alpha7 nAChRs and phosphorylated tau. To correlate expected cellular effects
with changes in hippocampal-dependent behaviors, we will also test for worsening of performance
in Y-maze, Morris water maze and novel object recognition assays. We will also perform
pharmacological experiments on neurons from AD model mice to extend our in vitro results, which
suggest that Ly6h and alpha7 nAChRs reciprocally regulate each other, and that amyloid beta
requires the open conformation of alpha7 to drive this process. Lastly, we will correlate Ly6h levels
in CSF and exosomes with disease severity in individual patients, and we will develop a rapid
ELISA assay to allow for related measurements to be made more routinely. Results from
experiments in our proposal will thus provide an integrated overview about how Ly6h functions at
a molecular, cellular and behavioral level to contribute to AD pathogenesis. At the same time our
experiments will also provide valuable clinical data and a new tool that may aid in earlier diagnosis
of AD.

## Key facts

- **NIH application ID:** 10754945
- **Project number:** 5R21AG080788-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** William J Joiner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $197,500
- **Award type:** 5
- **Project period:** 2022-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754945

## Citation

> US National Institutes of Health, RePORTER application 10754945, The contribution of Ly6h to Alzheimers Disease (5R21AG080788-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10754945. Licensed CC0.

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