# Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $34,010

## Abstract

Title and Abstract
The role of TREM1 signaling in the development of Alzheimer’s disease
Abstract
Recent systems biology studies and GWAS have confirmed a dominant role of microglial immune responses in
increasing risk of late onset Alzheimer’s disease (LOAD). In parallel, studies in AD model mice demonstrate
that healthy microglial function is lost with advancing amyloid pathology, and suggest that disease-modifying
components of the innate immune response could be targeted to slow or halt disease progression. In recent
transcriptome studies of AD model mice, we identified TREM1 as a gene highly induced in microglia and highly
correlated with microglial maladaptive responses. TREM1, and its anti-inflammatory relative TREM2, both
signal through DAP12, an adapter signaling protein that was recently identified in gene regulatory network
analyses as a top regulator of immune genes involved in increased risk of AD. Moreover, published data in
peripheral models of inflammation demonstrate a pivotal role of TREM1 in amplifying toxic aspects of the
innate immune response and worsening disease progression and outcome. Recent genetic studies of the
TREM1 locus demonstrate an intronic variant in TREM1 that is associated with increased CERAD pathology
and cognitive decline. In this proposal, we will test the role of TREM1 in worsening microglial immune
responses in models of AD. TREM1 is an inflammatory membrane receptor that is expressed on myeloid
lineage cells. TREM1 is unique in its function as a potent amplifier of inflammatory responses where it
generates a severe pro-inflammatory response only in association with activation of classical pattern
recognition receptors. Here, we will test the hypothesis that in the development of AD, TREM1 induces a
maladaptive microglial immune response to accumulating Aß peptide assemblies that accelerates synaptic and
neuronal injury and behavioral impairment. We will use a combination of in vitro pharmacologic and in vivo
conditional knockout strategies in AD model mice to test this hypothesis. Our studies will determine whether
TREM1 amplifies the maladaptive microglial response to accumulating Aß peptides, and whether TREM1 may
represent a novel immune target to slow progression to AD at pre-clinical and early clinical stages.

## Key facts

- **NIH application ID:** 10055756
- **Project number:** 3R01NS100180-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Katrin I. Andreasson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $34,010
- **Award type:** 3
- **Project period:** 2020-03-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055756

## Citation

> US National Institutes of Health, RePORTER application 10055756, Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia (3R01NS100180-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10055756. Licensed CC0.

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