Ping Bai, Prasenjit Mondal, Yan Liu, Ashley Gomm, Claire Suen, Liuyue Yang, Biyue Zhu, Haoqi Sun, Chongzhao Ran, Shiqian Shen, Rudolph E. Tanzi, Can Zhang, Changning Wang
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引用次数: 0
Abstract
INTRODUCTION
Alzheimer's disease (AD) is characterized by amyloid pathology and neuroinflammation, leading to cognitive decline. Targeting histone deacetylase-11 (HDAC11) offers a novel therapeutic strategy due to its role in immune regulation.
METHODS
We conducted neuropathological analyses on human AD post mortem brain tissues and 5xFAD transgenic mice. We developed PB94, a brain-permeable HDAC11-selective inhibitor, and assessed its effects using live-animal imaging and behavioral studies.
RESULTS
HDAC11 was significantly upregulated in AD brains, correlating with amyloid pathology and neuroinflammatory markers. PB94 treatment reduced amyloid burden and neuroinflammation, improving cognitive function in 5xFAD mice.
DISCUSSION
Our findings highlight HDAC11 as a promising drug target for AD. PB94's ability to reduce amyloid pathology and neuroinflammation suggests its potential as an effective therapeutic. This study supports further exploration of HDAC11 inhibition as a treatment strategy for AD.
Highlights
Histone deacetylase-11 (HDAC11) is significantly upregulated in Alzheimer's disease (AD) brains and colocalizes with amyloid pathology and neuroinflammatory markers.
Novel brain-permeable HDAC11-selective inhibitor PB94 demonstrates promising therapeutic potential for AD treatment.
PB94 treatment reduces amyloid burden and neuroinflammation in AD mouse models, confirmed by live imaging studies.
HDAC11 inhibition enhances microglial phagocytosis of amyloid beta proteins and modulates inflammatory cytokine levels.
PB94 treatment improves cognitive function in AD mouse models while showing favorable brain penetration and selectivity.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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