# Microglia dysregulation and SYK signaling in Alzheimer's disease

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $1,764,653

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease with dementia among the elderly,
yet exact causes of the disease and underlying pathogenic mechanisms that lead to development of effective
therapeutic interventions have not been identified. Recently, a number of genetic and transcriptomic studies in
humans and animal models highlight a critical, and possibly a disease-modifying role of microglia in AD. Once
activated, microglia are capable of displaying a spectrum of phenotypes ranging from homeostatic to
neurodegenerative phenotypes, with distinct transcriptomic signatures. However, it remains to be determined
which subset(s) of microglia are neuroprotective or detrimental, and how such microglia activation is driven by
what cellular mechanisms and disease conditions. We have strong evidence that microglia-enriched spleen
tyrosine kinase (SYK) critically controls the activation pattern of microglia. The cellular SYK signaling in
microglia is regulated by various cell-surface immunoreceptors including TREM2. The mechanistic details of
SYK activation as well as how its frequency, duration and patterns of activation determine above-mentioned
microglial phenotypes have not been elucidated. Here, we propose to test our novel hypothesis that SYK is
the key molecular hub that regulates a spectrum of microglia activation depending on the expression levels of
TREM2, age and the stage of Aβ pathology. We predict that activation of SYK, when its expression is
physiological in microglia, is neuroprotective and promotes effective containment and removal of Aβ, whereas
prolonged or chronic activation of SYK, especially when its expression is elevated in microglia, is detrimental
and drives pro-inflammatory and degenerative activation. In this proposal, we will first carefully investigate the
underlying mechanisms by which SYK controls several hallmark functions of microglia in various expression
levels of SYK and wildtype TREM2, as well as in the presence of TREM2 risk variant. We will then use an
animal model to determine if dichotomous activation of SYK depends on the Aβ plaque stages in two different
mouse models of AD. To test our hypothesis, we propose a combination of in vitro and in vivo studies utilizing
novel conditional transgenic mouse models and human iPSC-derived microglia (iMGL). The proposed research
will provide insight into whether and how SYK activation and activated microglia contribute to the disease
progression in AD. Furthermore, this proposal is feasible, highly-significant, and highly-relevant to the etiology
and progression of AD and we believe that the outcomes could have large public health impact, while
accelerating progress towards efficacious, therapeutic options for AD.

## Key facts

- **NIH application ID:** 10659670
- **Project number:** 1RF1AG078201-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Masashi Kitazawa
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,764,653
- **Award type:** 1
- **Project period:** 2023-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10659670

## Citation

> US National Institutes of Health, RePORTER application 10659670, Microglia dysregulation and SYK signaling in Alzheimer's disease (1RF1AG078201-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10659670. Licensed CC0.

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