Reducing PTP1B in the Hippocampus Protects Against Cognitive Decline in Prediabetes

IF 7.5 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2025-07-10 DOI:10.2337/db24-1167

Menglu Zhou, Xiaoying Yang, Xing Ge, Jiajia Chen, Wanyun Wu, Mingxuan Zheng, Xiaocheng Zhu, Xiaoying Cui, Renxian Tang, Kuiyang Zheng, Xu-Feng Huang, Libin Yao, Yinghua Yu

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Abstract

The prevalence of prediabetes is increasing globally, driven by rising obesity rates. Prediabetes increases the risk of neurodegenerative diseases, which are linked by neuroinflammation. Protein tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. However, the role and underlying mechanisms of PTP1B in prediabetes-induced cognitive impairment remain poorly understood. Here, we observed elevated levels of PTP1B in the serum of individuals with obesity and prediabetes. In mouse model of obesity and prediabetes induced by a high-fat, high-sugar diet (HFHSD), the PTP1B level was significantly increased in the hippocampus, correlating with cognitive decline, microglial activation, and inflammatory response. In a series of mouse models with selective PTP1B deletion, the loss of PTP1B in the hippocampus, hippocampal neurons, and leptin receptor–expressing cells reversed impairments of hippocampal leptin synaptic signaling, synaptic ultrastructure and associated proteins, and cognitive function in HFHSD-fed prediabetic mice. In a palmitic acid-induced, prediabetic, hippocampal neuronal model, genetic knockout or pharmacological inhibition of PTP1B effectively restored synaptic signaling and neurite outgrowth. These findings underscore the critical role of hippocampal neuronal PTP1B in mediating impairments of synaptic signaling leading to cognitive decline in prediabetes and suggest its significant therapeutic potential in addressing neurodegeneration. Article Highlights The present study reveals a previously unknown molecular mechanism linking prediabetes to neurodegeneration, addressing a critical gap in understanding metabolic-neurological interplay. We investigated whether PTP1B mediates prediabetes-induced cognitive impairment. PTP1B impaired synaptic signaling and synaptic ultrastructure in hippocampal neurons, contributing to cognitive decline in prediabetes. PTP1B is a novel therapeutic target for prediabetes-associated neurodegeneration.

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减少海马体中PTP1B可以防止前驱糖尿病患者的认知能力下降

在肥胖率上升的推动下，全球糖尿病前期患病率正在上升。前驱糖尿病增加了神经退行性疾病的风险，这与神经炎症有关。蛋白酪氨酸磷酸酶1B （PTP1B）是一种神经炎症和负性突触调节因子，参与神经退行性过程的发病机制。然而，PTP1B在糖尿病前期诱导的认知障碍中的作用和潜在机制仍然知之甚少。在这里，我们观察到肥胖和前驱糖尿病患者血清中PTP1B水平升高。在高脂高糖饮食（HFHSD）诱导的肥胖和前驱糖尿病小鼠模型中，海马PTP1B水平显著升高，与认知能力下降、小胶质细胞激活和炎症反应相关。在一系列选择性缺失PTP1B的小鼠模型中，在hfhsd喂养的前驱糖尿病小鼠中，海马、海马神经元和瘦素受体表达细胞中PTP1B的缺失逆转了海马瘦素突触信号、突触超微结构和相关蛋白以及认知功能的损伤。在棕榈酸诱导的前驱糖尿病海马神经元模型中，基因敲除或药理抑制PTP1B可有效恢复突触信号传导和神经突生长。这些发现强调了海马神经元PTP1B在介导导致前驱糖尿病认知能力下降的突触信号损伤中的关键作用，并表明其在解决神经变性方面具有重要的治疗潜力。本研究揭示了前驱糖尿病与神经退行性变之间先前未知的分子机制，解决了理解代谢-神经相互作用的关键空白。我们研究了PTP1B是否介导糖尿病前期诱导的认知障碍。PTP1B破坏海马神经元突触信号和突触超微结构，导致糖尿病前期认知能力下降。PTP1B是前驱糖尿病相关神经变性的新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.