MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity

作者：Pallavi Asthana, Liguo Li, Lin Lü, Jiayan Wu, Shuo Zhang, Ningning Li, Sheung Kin Ken Wong, Susma Gurung, Yijing Zhang, Yuwan Lin, Yufeng Peng, Zongtang Xu, Kui Ming Chan, Lixiang Zhai, Aiping Lü, Zhaoxiang Bian, Xin Ge, Ashok Iyaswamy, Man Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong · 发表于：Cell Discovery · 年份：2025 · DOI：10.1038/s41421-025-00825-w · 被引用次数：2 · 研究领域：Protease and Inhibitor Mechanisms、Neuropeptides and Animal Physiology、Neuroinflammation and Neurodegeneration Mechanisms

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, ...