Astrocyte-Specific Upregulation of Tumor Necrosis Factor Receptor II Ameliorates Pathological Phenotypes in APPNL-F/NL-F Mice
Dafeng Li1,2 · Yang Li1,2 · Lang Wen1,2 · Zuolong Chen1,2 · Feng Gao1,2,3 · Yong Shen1,2,3,4,5,6 · Qiong Wang1,2,3
1 Department of Neurology, I′nstitute on Aging and Brain Disorders, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230026, China
2 Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
3 Anhui Province Key Laboratory of Biomedical Aging Research, Hefei 230036, China
4 Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei 230026, China
5 Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026, China
6 Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
Abstract
Our earlier research showed that deletion of tumor necrosis factor-α receptor II (TNFRII) exacerbated Alzheimer’s disease (AD) associated pathology in the AD mouse model. Previous studies have demonstrated that TNFRII was mainly expressed in astrocytes. However, whether AD-associated pathology can be modified by targeting TNFRII in astrocytes remains unknown. Here, we showed that TNFRII was decreased in astrocytes in AD brains. Then, we developed transgenic mouse models (astrocyte-specific expression of human TNFRII mice, TNFRIIGFAP mice) and crossed TNFRIIGFAP mice with a mouse model of AD (humanized APP knock-in mice, APPNL-F/NL-F mice). We found that increased expression of TNFRII in astrocytes rescued learning and memory deficits, decreased amyloid burden, and reactive astrocytes in APPNL-F/NL-F mice. Mechanistically, APPNL-F/NL-F-TNFRIIGFAP mice displayed increased microgliosis, higher expression of plaque-associated microglial cluster of differentiation 68 (CD68), and enhanced microglial amyloid-β (Aβ) phagocytosis. In vitro assays confirmed that TNFRII upregulation in astrocytes enhanced phagocytosis of Aβ in BV2 murine microglial cell line (BV2) cells. Our study implicates that increased expression of TNFRII in astrocytes ameliorates pathology and behavioral deficits in APPNL-F/NL-F mice and provides new therapeutic options for AD.
Keywords
Alzheimer’s disease; Astrocytes; TNFRII; APPNL-F/NL-F mice
