# Common CD36-dependent gut-brain neuroimmune pathway regulates disruption of intestinal motility in Alzheimer's Disease

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $437,265

## Abstract

Abstract
Gastrointestinal (GI) disorders including constipation and fecal incontinence are commonly found in patients with
Alzheimer’s disease (AD), the most common cause of dementia. These same disorders are also frequently
encountered in the elderly, raising the possibility that a common process may underlie gut disturbances for both
AD and aging. In humans with AD and AD animal models, amyloid-β (Aβ) plaques, one of the disease hallmarks,
have been detected in the enteric nervous system (ENS), an autonomous branch of the peripheral nervous
system that spans the GI tract and regulates gut motility. Aβ gut accumulation appears to cause ENS
neuroinflammation and impaired gut contractility but current literature precludes definitive conclusion. Whether
and how AD involves the gut is of increasing importance given emerging reports that neurodegenerative
disorders are transmitted from the gut to the brain. The proposed multidisciplinary study will integrate the
science of AD with the basic biology of aging. We found that age-related changes to muscularis
macrophages (MMs), a population of tissue-resident macrophages in the ENS, drive geriatric ENS inflammation,
which is associated with disruption of GI motility. This MM alteration is regulated by the scavenger receptor CD36
and mirrors an AD diseased state found in microglia, the predominant macrophage population of the brain.
Following on these findings, we posit that a common CD36-dependent immune pathway in brain and gut
regulates ENS neuroinflammation and disruption of gut motility in AD. This hypothesis will be tested with
two aims performed in AD mouse models (APP/PS1 mice and Aβ-gut injected mice) in combination with CD36
knockout mice. First, the investigators will evaluate whether genetic deletion of CD36 inhibits Aβ induced
neuroimmune changes characterized by a shift in MMs from a tissue-protective, homeostatic state (HS) to a pro-
inflammatory geriatric state (GS). They will also assess whether CD36 deficiency inhibits AD-induced ENS
neuroinflammation characterized by infiltration of immune cells and elevated pro-inflammatory cytokines.
Second, the investigators will assess the impact of CD36 deficiency on AD-induced enteric neuron loss and
disruption of gut motility.
Successful completion of the proposed studies will identify a critical pathophysiological pathway in brain and gut
involved in neurodegenerative disease and aging. The results will inform novel prevention and intervention
strategies for AD-associated GI disorders.

## Key facts

- **NIH application ID:** 10448209
- **Project number:** 1R21AG077521-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Laren Becker
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $437,265
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448209

## Citation

> US National Institutes of Health, RePORTER application 10448209, Common CD36-dependent gut-brain neuroimmune pathway regulates disruption of intestinal motility in Alzheimer's Disease (1R21AG077521-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10448209. Licensed CC0.

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