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Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology.

ABSTRACT: Emerging evidence have posited that dysregulated microglia impair clearance and containment of amyloid-? (A?) species in the brain, resulting in aberrant buildup of A? and onset of Alzheimer's disease (AD). 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?-stimulated microglial phagocytosis, A? clearance, and resultant AD-like 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? oligomers-stimulated microglial phagocytosis. Whereas in Hck-deficient J20 mice, we observed exacerbated A? plaque burden, reduced microglial coverage, containment, and phagocytosis of A? plaques, and induced iNOS expression in plaque-associated 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-like 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.

SUBMITTER: Lim SL

PROVIDER: S-EPMC6645690 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology.

Lim Siok Lam SL Tran Diana Nguyen DN Zumkehr Joannee J Chen Christine C Ghiaar Sagar S Kieu Zanett Z Villanueva Emmanuel E Gallup Victoria V Rodriguez-Ortiz Carlos J CJ Kitazawa Masashi M

Glia 20180912 12

Emerging evidence have posited that dysregulated microglia impair clearance and containment of amyloid-β (Aβ) species in the brain, resulting in aberrant buildup of Aβ and onset of Alzheimer's disease (AD). 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 pharm ...[more]

PMID: 30277607

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Project description:The p38 alpha mitogen-activated protein kinase (p38α) is linked to both innate and adaptive immune responses and is under investigation as a target for drug development in the context of Alzheimer's disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38α inhibition can protect against AD-associated neuropathology, the underlying mechanisms are not fully elucidated. Inhibitors of p38α may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to AD pathology. The present study tests this hypothesis by knocking out microglial p38α and assessing early-stage pathological changes. Conditional knockout of microglial p38α was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system under control of the Cx3cr1 promoter. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field, followed by a later radial arm water maze test and collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included quantification of proinflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics. Loss of microglial p38α did not alter behavioral outcomes, proinflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Aβ42 and reduce colocalization of Iba1 and 6E10 in a subset of microglia in close proximity to plaques. The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38α inhibition in the context of early AD-type amyloid pathology is a subtle alteration of microglia-plaque interactions. Encouragingly from a therapeutic standpoint, these data suggest no detrimental effect of even substantial decreases in microglial p38α in this context. Additionally, these results support future investigations of microglial p38α signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.

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Dataset Information

Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology.

Publications

Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology.

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