Soluble TGF‐β decoy receptor TGFBR3 exacerbates Alzheimer's disease pathology by modifying microglial function

Author:

Zhou Lijun1ORCID,Wang Nan12,Feng Wenzheng1,Liu Xin12,Wu Qiong2,Chen Jiangxia1,Jiao Xinming1,Ning Xinyue1,Qi Zhentong1,Xu Zihua12,Jiang Xiaowen3,Zhao Qingchun12

Affiliation:

1. Department of Clinical Pharmacy Shenyang Pharmaceutical University Shenyang People's Republic of China

2. Department of Pharmacy General Hospital of Northern Theater Command Shenyang People's Republic of China

3. College of Traditional Chinese Pharmacy Shenyang Pharmaceutical University Shenyang People's Republic of China

Abstract

AbstractAlzheimer's disease (AD) is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction. However, the molecular mechanisms are not fully understood. To elucidate the molecular mechanism contributing to AD, an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA‐sequencing (RNA‐seq) data of the temporal cortex from AD patients. Soluble transforming growth factor beta receptor 3 (sTGFBR3) was identified as a critical target in AD, which was abnormally elevated in AD patients and AD mouse models. We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein (APP)/PS1 and streptozotocin (STZ)‐induced neuronal impairment mice after its expression was disrupted by a lentiviral (LV) vector expressing shRNA. Mechanistically, sTGFBR3 deficiency augments TGF‐β signaling and suppressing the NF‐κB pathway, thereby reduced the number of disease‐associated microglia (DAMs), inhibited proinflammatory activity and increased the phagocytic activity of DAMs. Moreover, sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide (LPS) and alleviated neuronal dysfunction induced by STZ. Collectively, these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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