# Modulating microglial function to restore A-beta proteostasis in Alzheimer's Disease

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $625,144

## Abstract

PROJECT SUMMARY / ABSTRACT
 Alzheimer’s Disease is a debilitating degenerative disease without effective treatment that is increasing in
prevalence. Developing effective therapies has been impeded because the underlying biological mechanisms
driving disease pathogenesis are still poorly understood. Abnormal cleavage of amyloid precursor protein
(APP) that generates aggregating forms of neurotoxic amyloid-beta (Aβ) protein has been a focus of
investigation for many years. Although very rare forms of early onset familial AD caused by mutations in APP
or processing-associated proteins PSEN1 and PSEN2 substantiate a role for Aβ in the pathogenesis of AD,
most cases (>95%) have no definitive genetic cause. Many risk-associated genes (>26) have been identified,
but the role of most of them in AD pathogenesis remains very poorly understood. Microglia are resident innate
immune cells that mediate persistent neuroinflammatory responses to Aβ protein characterized by increased
inflammatory cytokine production, synapse loss and neurotoxicity. Many of the identified risk-associated genes
appear to encode proteins that are expressed in microglia and involved in phagocytosis and endolysosomal
trafficking and proteolytic degradation, raising the possibility that fundamental abnormalities in microglia may
contribute to poor Aβ processing and persistent neuroinflammation that leads to neurotoxicity and
neurodegeneration in AD.
 Angiotensin Converting Enzyme (ACE) is a very poorly studied risk-associated gene. Previous studies
published by us and strong preliminary data indicate that it has a significant role in Aβ clearance from the brain
and in enhancing Aβ protein phagocytosis, its endolysosomal trafficking and proteolytic degradation in
microglia. The project is outlined in three specific aims to: (1) examine the role of ACE specifically in microglia
in novel transgenic mice and in an animal model of AD, (2) examine the molecular mechanisms of ACE-
regulated gene expression in microglia and determine their role in phagocytosis, endolysosomal trafficking and
proteolytic degradation and (3) characterize the function of ACE in human induced microglia engrafted into
mice brains to study their response in vivo in a model of AD.
 Millions of humans are afflicted with AD, yet prevention and treatment remain very poor. We anticipate that
these studies focused on the AD risk-associated gene ACE and its role in Aβ processing in microglia will
identify novel signaling pathways that enhance Aβ protein processing. Moreover, we anticipate that these
studies may elucidate mechanisms in microglia that may be exploited to develop treatments to enhance Aβ
proteostasis and mitigate neuroinflammation in the brain in AD.

## Key facts

- **NIH application ID:** 10891782
- **Project number:** 4R01AG074365-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** WARREN G TOURTELLOTTE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,144
- **Award type:** 4N
- **Project period:** 2021-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891782

## Citation

> US National Institutes of Health, RePORTER application 10891782, Modulating microglial function to restore A-beta proteostasis in Alzheimer's Disease (4R01AG074365-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891782. Licensed CC0.

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