当前位置: X-MOL 学术Acta Neuropathol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
PTEN activation contributes to neuronal and synaptic engulfment by microglia in tauopathy.
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2020-03-31 , DOI: 10.1007/s00401-020-02151-9
Joseph Benetatos 1 , Rachel E Bennett 2 , Harrison T Evans 1 , Sevannah A Ellis 1 , Bradley T Hyman 2 , Liviu-Gabriel Bodea 1 , Jürgen Götz 1
Affiliation  

Phosphatase and tensin homolog (PTEN) regulates synaptic density in development; however, whether PTEN also regulates synapse loss in a neurodegenerative disorder such as frontotemporal lobar degeneration with Tau deposition (FTLD-Tau) has not been explored. Here, we found that pathological Tau promotes early activation of PTEN, which precedes apoptotic caspase-3 cleavage in the rTg4510 mouse model of FTLD-Tau. We further demonstrate increased synaptic and neuronal exposure of the apoptotic signal phosphatidylserine that tags neuronal structures for microglial uptake, thereby linking PTEN activation to synaptic and neuronal structure elimination. By applying pharmacological inhibition of PTEN's protein phosphatase activity, we observed that microglial uptake can be decreased in Tau transgenic mice. Finally, we reveal a dichotomous relationship between PTEN activation and age in FTLD-Tau patients and healthy controls. Together, our findings suggest that in tauopathy, PTEN has a role in the synaptotoxicity of pathological Tau and promotes microglial removal of affected neuronal structures.

中文翻译:

PTEN 激活有助于小胶质细胞在 tau 蛋白病中吞噬神经元和突触。

磷酸酶和张力蛋白同源物 (PTEN) 在发育过程中调节突触密度;然而,尚未探索 PTEN 是否也调节神经退行性疾病中的突触丢失,例如伴有 Tau 沉积的额颞叶变性 (FTLD-Tau)。在这里,我们发现病理性 Tau 促进 PTEN 的早期激活,这在 FTLD-Tau 的 rTg4510 小鼠模型中的凋亡 caspase-3 裂解之前。我们进一步证明了凋亡信号磷脂酰丝氨酸的突触和神经元暴露增加,该信号为小胶质细胞摄取标记神经元结构,从而将 PTEN 激活与突触和神经元结构消除联系起来。通过对 PTEN 的蛋白磷酸酶活性进行药理学抑制,我们观察到 Tau 转基因小鼠的小胶质细胞摄取可以减少。最后,我们揭示了 FTLD-Tau 患者和健康对照的 PTEN 激活与年龄之间的二分关系。总之,我们的研究结果表明,在 tau 蛋白病变中,PTEN 在病理性 Tau 蛋白的突触毒性中起作用,并促进受影响神经元结构的小胶质细胞去除。
更新日期:2020-04-20
down
wechat
bug