1. Genetic Ablation of Hematopoietic Cell Kinase Accelerates Alzheimer’s Disease–Like Neuropathology in Tg2576 Mice
- Author
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Lim, Siok Lam, Tran, Diana Nguyen, Kieu, Zanett, Chen, Christine, Villanueva, Emmanuel, Ghiaar, Sagar, Gallup, Victoria, Zumkehr, Joannee, Cribbs, David H, Rodriguez-Ortiz, Carlos J, and Kitazawa, Masashi
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Aging ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Brain Disorders ,Dementia ,Neurosciences ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Alzheimer Disease ,Amyloid beta-Peptides ,Animals ,Disease Models ,Animal ,Disease Progression ,Exploratory Behavior ,Female ,Homeostasis ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mice ,Transgenic ,Microglia ,Morris Water Maze Test ,Myeloid Cells ,Neuroimmunomodulation ,Phagocytosis ,Plaque ,Amyloid ,Proto-Oncogene Proteins c-hck ,Recognition ,Psychology ,Alzheimer's disease ,Hematopoietic cell kinase ,Amyloid-beta ,Tg2576 mice ,Alzheimer’s disease ,Amyloid-β ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
Microglial dysregulation, pertaining to impairment in phagocytosis, clearance and containment of amyloid-β (Aβ), and activation of neuroinflammation, has been posited to contribute to the pathogenesis of Alzheimer's disease (AD). Detailed cellular mechanisms that are disrupted during the disease course to display such impairment in microglia, however, remain largely undetermined. We hypothesize that loss of hematopoietic cell kinase (HCK), a phagocytosis-regulating member of the Src family tyrosine kinases that mediate signals from triggering receptor expressed on myeloid cells 2 and other immunoreceptors, impairs microglial homeostasis and Aβ clearance, leading to the accelerated buildup of Aβ pathology and cognitive decline during the early stage of neuropathological development. To elucidate the pivotal role of HCK in AD, we generated a constitutive knockout of HCK in the Tg2576 mouse model of AD. We found that HCK deficiency accelerated cognitive decline along with elevated Aβ level and plaque burden, attenuated microglial Aβ phagocytosis, induced iNOS expression in microglial clusters, and reduced pre-synaptic protein at the hippocampal regions. Our findings substantiate that HCK plays a prominent role in regulating microglial neuroprotective functions and attenuating early AD neuropathology.
- Published
- 2020