MPTP公司
线粒体通透性转换孔
线粒体
粒体自噬
伊布塞伦
神经炎症
神经退行性变
生物能学
生物
β淀粉样蛋白
药理学
阿尔茨海默病
细胞生物学
神经科学
化学
程序性细胞死亡
生物化学
氧化应激
医学
病理
自噬
超氧化物歧化酶
免疫学
疾病
谷胱甘肽过氧化物酶
炎症
肽
细胞凋亡
多巴胺
多巴胺能
作者
Sourav Samanta,Firoz Akhter,Anuradha Roy,Doris Chen,Benjamin Turner,Yongfu Wang,Nicolina Clemente,Chunyu Wang,Russell H. Swerdlow,Kevin P. Battaile,Scott Lovell,Shi Fang Yan,Shirley ShiDu Yan
出处
期刊:Brain
[Oxford University Press]
日期:2023-12-26
被引量:1
标识
DOI:10.1093/brain/awad432
摘要
Mitochondrial dysfunction is an early pathological feature of Alzheimer disease (AD) and plays a crucial role in the development and progression of AD. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore (mPTP), leading to mitochondrial dysfunction and cell death. Blocking mPTP opening by inhibiting CypD activity is a promising therapeutic approach for AD. However, there is currently no effective CypD inhibitor for AD, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility, and low selectivity. Here, we report a new class of nontoxic and biocompatible CypD inhibitor, Ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-Ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on AD mitochondrial and glycolytic bioenergetics in AD-derived mitochondrial cybrid cells, an ex-vivo human sporadic AD mitochondrial model, and on synaptic function, inflammatory response, and learning and memory in AD mouse models. Inhibition of CypD by Ebselen protects against sporadic AD- and amyloid beta (Aβ)-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of AD mouse models, which is linked to CypD-related mPTP formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including AD, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
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