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

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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 microhemorrhages in collaboration with the Kipnis and Randolph labs. Through integration with projects 1, 2, 3 and Core B, Project 4 will provide deep comprehension of mechanisms underlying microglia and PBM responses in AD and CAA and unearth a novel therapeutic target.