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Hematopoietic cell kinase (Hck) is one of the key regulators of phagocytosis among the Src family tyrosine kinases (SFKs) in myeloid cells, and its expression is found to be significantly altered in AD brains. However, the role of Hck signaling in AD pathogenesis is unknown. We employed pharmacological inhibition and genetic ablation of Hck in BV2 microglial cells and J20 mouse model of AD, respectively, to evaluate the impact of Hck deficiency on A\u03b2\u2010stimulated microglial phagocytosis, A\u03b2 clearance, and resultant AD\u2010like neuropathology. Our in vitro data reveal that pharmacological inhibition of SFKs\/Hck in BV2 cells and genetic ablation of their downstream kinase, spleen tyrosine kinase (Syk), in primary microglia significantly attenuate A\u03b2 oligomers\u2010stimulated microglial phagocytosis. Whereas in Hck\u2010deficient J20 mice, we observed exacerbated A\u03b2 plaque burden, reduced microglial coverage, containment, and phagocytosis of A\u03b2 plaques, and induced iNOS expression in plaque\u2010associated microglial clusters. These multifactorial changes in microglial activities led to attenuated PSD95 levels in hippocampal DG and CA3 regions, but did not alter the postsynaptic dendritic spine morphology at the CA1 region nor cognitive function of the mice. Hck inhibition thus accelerates early stage AD\u2010like neuropathology by dysregulating microglial function and inducing neuroinflammation. Our data implicate that Hck pathway plays a prominent role in regulating microglial neuroprotective function during the early stage of AD development.<\/jats:p>","DOI":"10.1002\/glia.23522","type":"journal-article","created":{"date-parts":[[2018,9,12]],"date-time":"2018-09-12T20:25:35Z","timestamp":1536783935000},"page":"2700-2718","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease\u2010like neuropathology"],"prefix":"10.1002","volume":"66","author":[{"given":"Siok Lam","family":"Lim","sequence":"first","affiliation":[{"name":"Center for Occupational and Environmental Health, Department of Medicine University of California  Irvine California"},{"name":"Molecular and Cell Biology University of California  Merced California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana 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