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

IF 12.5 1区 生物学 Q1 CELL BIOLOGY
Pallavi Asthana, Liguo Li, Lin Lu, 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 Lyu, Zhao-Xiang Bian, Xin Ge, Ashok Iyaswamy, Min Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong
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Abstract

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, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

MT1-MMP抑制使老化的大脑恢复活力,并挽救肥胖的认知缺陷。
肥胖与晚年认知障碍和痴呆的风险增加有关。尽管衰老和肥胖都与认知能力下降有关,但目前尚不清楚它们如何相互作用,影响整个生命周期的认知功能,以及大脑功能如何调节它们与认知能力的关系。我们之前的研究和其他研究表明,膜型1-基质金属蛋白酶(MT1-MMP/MMP14)随着年龄的增长而增加,调节能量稳态。抑制MT1-MMP可改善胰岛素敏感性,减少体脂,降低血清胆固醇。在这里,我们证明了MT1-MMP将神经炎症与衰老和肥胖的认知能力下降联系起来。大脑中的炎症反应增加了小鼠和人类海马中MT1-MMP的激活。海马MT1-MMP单独激活可以独立于神经炎症引发认知能力下降和突触损伤。相反,海马中MT1-MMP的消融可以逆转认知能力下降,并改善衰老和肥胖患者的突触可塑性。通过口服脑渗透抑制剂或向海马体靶向递送一种中和抗体,对MT1-MMP进行药理学抑制,可改善老年和肥胖小鼠的记忆和学习能力,且无毒性。从机制上说,MT1-MMP蛋白可使g蛋白偶联受体158 (GPR158)失活,从而抑制OCN-GPR158轴在衰老和肥胖中促进认知的能力,GPR158是骨钙素(OCN)的海马受体,对维持认知完整性很重要。这些发现提示了海马功能障碍的新机制,并揭示了单一mt1 - mmp阻断剂治疗多种年龄相关疾病的潜力,包括神经退行性疾病、肥胖、糖尿病和动脉粥样硬化。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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