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.