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.

中文翻译：

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造血细胞激酶的基因消融加速 Tg2576 小鼠的阿尔茨海默病样神经病理学。

小胶质细胞失调，与吞噬功能受损、淀粉样蛋白-β (Aβ) 的清除和遏制以及神经炎症的激活有关，已被认为有助于阿尔茨海默病 (AD) 的发病机制。然而，在疾病过程中被破坏以在小胶质细胞中显示这种损伤的详细细胞机制在很大程度上仍未确定。我们假设造血细胞激酶 (HCK) 是 Src 家族酪氨酸激酶的吞噬作用调节成员，它介导来自髓细胞 2 和其他免疫受体上表达的触发受体的信号，这会损害小胶质细胞的稳态和 Aβ 清除，导致加速积聚神经病理学发展早期 Aβ 病理学和认知能力下降的研究。为了阐明 HCK 在 AD 中的关键作用，我们在 AD 的 Tg2576 小鼠模型中产生了 HCK 的组成型敲除。我们发现 HCK 缺乏会加速认知能力下降以及 Aβ 水平和斑块负荷的升高，减弱小胶质细胞 Aβ 的吞噬作用，诱导小胶质细胞簇中的 iNOS 表达，并减少海马区的突触前蛋白。我们的研究结果证实 HCK 在调节小胶质细胞神经保护功能和减轻早期 AD 神经病理学方面发挥着重要作用。