Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology.
Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology.
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作者：
Lim SL;Tran DN;Zumkehr J;Chen C;Ghiaar S;Kieu Z;Villanueva E;Gallup V;Rodriguez-Ortiz CJ;Kitazawa M
新出现的证据已经假定，失调的小胶质细胞损害大脑中淀粉样蛋白-β（Aβ）种类的清除和遏制，导致Aβ的异常积聚和阿尔茨海默病（AD）的发作。造血细胞激酶（Hck）是骨髓细胞中Src家族酪氨酸激酶（SFKs）中吞噬作用的关键调节因子之一，并且发现其表达在AD脑中显著改变。然而，Hck信号在AD发病机制中的作用尚不清楚。我们分别在BV 2小胶质细胞和J20 AD小鼠模型中采用药理学抑制和基因消融Hck，以评估Hck缺乏对Aβ刺激的小胶质细胞吞噬、Aβ清除和由此产生的AD样神经病理学的影响。我们的体外数据显示，药理学抑制BV 2细胞中的SFKs/Hck及其下游激酶脾酪氨酸激酶（Syk）的基因消融可显著减弱Aβ寡聚体刺激的小胶质细胞吞噬作用。而在Hck缺陷的J20小鼠中，我们观察到Aβ斑块负荷加重，小胶质细胞覆盖减少，Aβ斑块的容纳和吞噬减少，并诱导斑块相关小胶质细胞簇中的iNOS表达。小胶质细胞活动的这些多因素变化导致海马DG和CA 3区的PSD 95水平降低，但没有改变CA 1区的突触后树突棘形态，也没有改变小鼠的认知功能。因此，Hck抑制通过失调小胶质细胞功能和诱导神经炎症来加速早期AD样神经病理学。我们的数据暗示，HCK通路在调节AD发展的早期阶段的小胶质细胞神经保护功能中起着突出的作用。
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.
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影响因子：
3.9
作者：
Kopec, KK;Carroll, RT
通讯作者：
Carroll, RT
影响因子：
5.3
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
通讯作者：
Vitorica, Javier
DOI：
10.4049/jimmunol.1100620
发表时间：
2011-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kitazawa M;Cheng D;Tsukamoto MR;Koike MA;Wes PD;Vasilevko V;Cribbs DH;LaFerla FM
通讯作者：
LaFerla FM
影响因子：
5.3
作者：
Koenigsknecht, J;Landreth, G
通讯作者：
Landreth, G
影响因子：
5.3
作者：
Kim, Woojin S.;Li, Hongyun;Garner, Brett
通讯作者：
Garner, Brett