# Microglial gene regulation and phagocytosis in prodromal Alzheimer's Disease

> **NIH NIH P20** · UNIVERSITY OF NEVADA LAS VEGAS · 2020 · $370,778

## Abstract

ABSTRACT:
Alzheimer's disease (AD) is the leading cause of dementia, affecting more than 5 million older people in the U.S.
alone. It is imperative to define the earliest cellular functions and molecular mechanisms driving the earliest
pathogenesis in prodromal AD, mild cognitive impairment (MCI). Microglia, the primary brain immune cells, have
been implicated as playing an important role in the development of AD. Genetic studies indicate that genetic risk
factors associated with the disease are highly expressed in microglia. TREM2, a receptor expressed exclusively
on microglia, is at the top of the risk gene list. In response to Aβ deposition, microglia become activated and
adopt a series of gene expression profiles and pathways specifically linked to neuroinflammation. Activated
microglia release pro-inflammatory cytokines and neurotoxic proteins that cause pathologic neurodegeneration.
Therefore, microglial gene signaling is believed to serve as a key regulator that allows microglia to switch from
a homeostatic to a disease-associated state. However, whether microglia exert either beneficial or detrimental
effects in AD pathology may depend on the disease stage, and the exact cellular functions and molecular
mechanisms are unknown due to the lack of a microglia model of the disease continuum. In this study, we
propose using advanced tools (a patient-specific microglia model and engineered protein chimeras) to study
microglial gene regulation and phagocytic activities during prodromal AD (MCI). Our long-term goal is to develop
novel disease-modifying therapies for early intervention for AD. Our hypothesis is that microglial gene expression
and phagocytosis play important roles in the early development of AD. To test this hypothesis, we propose two
pilot projects for this proposal. Project 1: Patient-specific induced microglial modeling of gene regulation
for prodromal AD (MCI). Project 2: TREM2-mediated phagocytic clearance of Aβ amyloid in mice. The
patient-specific microglia model would vastly accelerate the rate of discovery of genes, pathways, and functions
associated with AD. With this cellular model, in conjunction with the AD studies supported by the CNTN COBRE,
we will be able to dissect the microglia molecular signatures linked to Aβ pathology and their functional changes
to shed light on the pathology of AD. Focusing specifically on patients with MCI rather than AD will allow us to
understand the mechanisms inherent in early-stage disease instead of focusing on syndromic dementia when
the disease is more resistant to therapy. Moreover, harnessing the therapeutic potential of protein chimeras
designed to facilitate anti-inflammatory microglial phagocytosis of β-amyloid via TREM2 may prevent microglial
activation and will result in a reduced immune response. If successful, the protein chimeras will be tested as a
potential therapy for AD. The proposed collaborative studies will stimulate additional collaborations among
project leaders, ...

## Key facts

- **NIH application ID:** 10123373
- **Project number:** 3P20GM121325-03S1
- **Recipient organization:** UNIVERSITY OF NEVADA LAS VEGAS
- **Principal Investigator:** MARTIN R SCHILLER
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,778
- **Award type:** 3
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123373

## Citation

> US National Institutes of Health, RePORTER application 10123373, Microglial gene regulation and phagocytosis in prodromal Alzheimer's Disease (3P20GM121325-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123373. Licensed CC0.

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