# The protein tyrosine kinase SYK drives innate immune responses against Alzheimer's Disease

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2022 · $612,910

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is the most common cause of dementia. Pathological hallmarks of AD are extracellular
amyloid-β (Aβ) plaques, intraneuronal neurofibrillary tangles of tau aggregates, and neuronal death. There are
no approved therapies that can halt or reverse AD progression. The greatest risk factors of AD include age and
genetics. Among genetic risk factors, a DNA variant of the receptor TREM2, TREM2R47H, impairs the ability of
microglia to restrict spreading of Aβ plaques. TREM2 transmits intracellular signals through the adaptor DAP12
that recruits the protein tyrosine kinase SYK, which promotes tyrosine phosphorylation of multiple downstream
mediators. Highlighting the importance of SYK signaling in AD, microglia associated with Aβ plaques upregulate
the expression of CD300LB, CD200R4, and CLEC7A, all of which activate SYK either through DAP12 or by
directly recruiting SYK. However, not much is known about SYK signaling in AD. Project 4 will explore this black
box, elucidating the impact of SYK on microglia and parenchymal border macrophage (PBM) function in AD and
cerebral amyloid angiopathy (CAA) models. Aim 1 will test the hypothesis that SYK is a major driver of microglia
responses to Aβ and tau. Our preliminary data indicate that SYK deficiency impairs microglia clustering around
Aβ plaques, which facilitates Aβ accumulation, neurite dystrophy and memory deficits. Moreover, SYK-deficient
microglia show evidence of increased autophagy and lipid dysmetabolism. However, microglia proliferation and
ApoE production are maintained through a SYK-independent pathway. Based on these premises, we will test
the following hypotheses: a) microglia require SYK to control both Aβ and tau pathology; b) SYK-deficient
microglia are impaired because of a major metabolic defect involving the mTOR pathway, autophagy and lipid
metabolism; c) ApoE production and proliferation of SYK-deficient microglia are sustained by a DAP10 pathway
associated with TREM2. Aim 2 will test the hypothesis that SYK activation by anti-CLEC7A alleviates Aβ
pathology. Our preliminary data demonstrate that engagement of CLEC7A rescues microglia activation in the
TREM2R47H-5xFAD model, in which microglia are defective due to the TREM2 variant. CLEC7A is a C-type lectin
receptor that directly recruits SYK and is expressed by microglia in mice with AD pathology. To test our
hypothesis, we will determine whether systemic administration of an anti-CLEC7A antibody as a surrogate ligand
ameliorates pathology and behavior in TREM2R47H-5xFAD mice. Aim 3 will test the hypothesis that PBMs require
SYK to clear Aβ in CAA. Our preliminary data demonstrate that PBMs express SYK. PBMs have been shown to
diminish the Aβ load in CAA independently of microglia. We will test our hypothesis in a model for CAA, 5xFAD-
APOE4 mice, crossed with mice lacking SYK in PBMs. We will assess vascular amyloid pathology, vasomotion
by photoacoustic imaging and 2P-microscopy, as well as micr...

## Key facts

- **NIH application ID:** 10492260
- **Project number:** 1P01AG078106-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARCO COLONNA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $612,910
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492260

## Citation

> US National Institutes of Health, RePORTER application 10492260, The protein tyrosine kinase SYK drives innate immune responses against Alzheimer's Disease (1P01AG078106-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10492260. Licensed CC0.

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