美国布莱根妇女医院Oleg Butovsky研究组发现，APOE4通过诱导转化生长因子-β (TGFβ)介导的检查点削弱阿尔茨海默病(AD)的小胶质细胞应答。这一研究成果发表在2023年9月25日出版的国际学术期刊《自然—免疫学》上。

他们在小鼠和人类中显示了小胶质细胞APOE4在诱导神经退行性小胶质细胞(MGnD)对神经变性反应中的负作用。在P301S tau转基因小鼠中，小胶质细胞APOE4的缺失恢复了与神经保护相关的MGnD表型，并降低了APP/PS1小鼠的病理。小胶质细胞APOE4缺失后，与β-淀粉样蛋白(Aβ)斑块包封和清除相关的MGnD -星形胶质细胞串导通过LGALS3信号介导。在携带APOE4等位基因的AD供者的大脑中，他们发现与APOE3等位基因纯合的个体相比，女性中MGnD基因(包括LGALS3)的抑制与性别依赖的AD危险因素的相互诱导相关。

在机制上，APOE4介导的ITGB8 TGFβ信号传导通过上调小鼠小胶质稳态检查点(包括Inpp5d)来削弱MGnD应答。APP/PS1小鼠小胶质细胞中Inpp5d的缺失可恢复MGnD -星形胶质细胞串导，促进斑块清除。他们发现小胶质APOE4–ITGB8–TGFβ通路是小胶质对AD病理反应的负调节因子，通过阻断ITGB8–TGFβ信号通路恢复MGnD表型为AD的治疗干预提供了有希望的治疗干预。

据悉，APOE4等位基因是迟发性AD最强的遗传危险因素。尽管APOE在MGnD中表达最丰富，但小胶质细胞APOE4在AD发病中的作用尚不清楚。

附：英文原文

Title: APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints

Author: Yin, Zhuoran, Rosenzweig, Neta, Kleemann, Kilian L., Zhang, Xiaoming, Brando, Wesley, Margeta, Milica A., Schroeder, Caitlin, Sivanathan, Kisha N., Silveira, Sebastian, Gauthier, Christian, Mallah, Dania, Pitts, Kristen M., Durao, Ana, Herron, Shawn, Shorey, Hannah, Cheng, Yiran, Barry, Jen-Li, Krishnan, Rajesh K., Wakelin, Sam, Rhee, Jared, Yung, Anthony, Aronchik, Michael, Wang, Chao, Jain, Nimansha, Bao, Xin, Gerrits, Emma, Brouwer, Nieske, Deik, Amy, Tenen, Daniel G., Ikezu, Tsuneya, Santander, Nicolas G., McKinsey, Gabriel L., Baufeld, Caroline, Sheppard, Dean, Krasemann, Susanne, Nowarski, Roni, Eggen, Bart J. L., Clish, Clary, Tanzi, Rudolph E., Madore, Charlotte, Arnold, Thomas D., Holtzman, David M., Butovsky, Oleg

Issue&Volume: 2023-09-25

Abstract: The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD–astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8–transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD–astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4–ITGB8–TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8–TGFβ signaling provides a promising therapeutic intervention for AD.

DOI: 10.1038/s41590-023-01627-6

Source: https://www.nature.com/articles/s41590-023-01627-6