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-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 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 Aβ-stimulated microglial phagocytosis, Aβ 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 Aβ oligomers-stimulated microglial phagocytosis. Whereas in Hck-deficient J20 mice, we observed exacerbated Aβ plaque burden, reduced microglial coverage, containment and phagocytosis of Aβ 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 post-synaptic dendritic spine morphology at the CA1 region nor cognition 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.

Alleviation of Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Rats by Yiqi Huayu Jiedu Decoction: A Tandem Mass Tag-Based Proteomics Study

“…Studies have shown that Hck deficiency weakens the phagocytic function of microglia a β ( Lim et al., 2020 ). Hck is one of the key regulators of phagocytosis among the Src family tyrosine kinases (SFKs) in myeloid cells and combined absence of the Src family kinases Hck drastically impairs phagocytosis ( Lim et al., 2018 ; Lőrincz et al., 2019 ). Drugs could inhibit Marcks expression, consequently, blocking Fc gamma receptor-mediated phagocytosis pathway, which contributed to the cancer progression in vitro and in vivo ( Luo et al., 2019 ).…”

Single Cell-type Integrative Network Modeling Identified Novel Microglial-specific Targets for the Phagosome in Alzheimer’s disease

“…Comparative profiling of human cortical gene expression in AD patients [35] and mouse models with amyloid beta plaque accumulation have shown involvement of our key drivers LAPTM5, FCER1G and HCK. These three genes were identified in Zhang et al shows that inhibition of HCK dysregulates microglial function of phagocytosis and enhances amyloid plaque build-up in the J-20 mouse model of AD [92]. In addition, a recent study [41] showed that LAPTM5 is significantly associated with the mouse amyloid response network and that it's human ortholog contains SNPs associated with AD.…”

Alzheimer’s disease: insights from a network medicine perspective

“…Another member of Src family of tyrosine kinases is the HCK proto-oncogene, Src family tyrosine kinase (HCK). In particular, HCK is a hematopoietic cell kinase whose dysregulation may affect microglia (i.e., resident immune cells in the central nervous system playing critical roles in brain immunity, development, and homeostasis) and accelerate early stage Alzheimer's disease-like neuropathology 46 . Recently, also the colony stimulating factor 3 receptor (CSF3R) and the docking protein 3 (DOK3) was found to be involved in the in microglial cell activation 47 , 48 .…”