Overexpression of forebrain PTP1B leads to synaptic and cognitive impairments in obesity

Brain Behav Immun. 2024 Feb 8;117:456-470. doi: 10.1016/j.bbi.2024.02.008. Online ahead of print.ABSTRACTObesity has reached pandemic proportions and is a risk factor for neurodegenerative diseases, including Alzheimer's disease. Chronic inflammation is common in obese patients, but the mechanism between inflammation and cognitive impairment in obesity remains unclear. Accumulative evidence shows that protein-tyrosine phosphatase 1B (PTP1B), a neuroinflammatory and negative synaptic regulator, is involved in the pathogenesis of neurodegenerative processes. We investigated the causal role of PTP1B in obesity-induced cognitive impairment and the beneficial effect of PTP1B inhibitors in counteracting impairments of cognition, neural morphology, and signaling. We showed that obese individuals had negative relationship between serum PTP1B levels and cognitive function. Furthermore, the PTP1B level in the forebrain increased in patients with neurodegenerative diseases and obese cognitive impairment mice with the expansion of white matter, neuroinflammation and brain atrophy. PTP1B globally or forebrain-specific knockout mice on an obesogenic high-fat diet showed enhanced cognition and improved synaptic ultrastructure and proteins in the forebrain. Specifically, deleting PTP1B in leptin receptor-expressing cells improved leptin synaptic signaling and increased BDNF expression in the forebrain of obese mice. Importantly, we found that various PTP1B allosteric inhibitors (e.g., MSI-14...

Source: Brain, Behavior, and Immunity - February 9, 2024 Category: Neurology Authors: Xing Ge Minmin Hu Menglu Zhou Xiaoli Fang Xi Chen Deqin Geng Li Wang Xiaoying Yang Huimei An Meng Zhang Danhong Lin Mingxuan Zheng Xiaoying Cui Qing Wang Yuqing Wu Kuiyang Zheng Xu-Feng Huang Yinghua Yu Source Type: research