Alzheimer's & dementia : the journal of the Alzheimer's Association
H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis
By Fuchs DT, Vit JP, Rentsendorj A and 18 others.
Abstract
Introduction
Epigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear.
Methods
We quantified the repressive epigenetic mark histone H3 lysine 9 trimethylation (H3K9me3) in post mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. Using a multi-enzyme methyltransferase panel, we characterized the in vitro inhibitory activity of ETP69, an epidithiodiketopiperazine, against suppressor of variegation 3-9 homologue 1 (SUV39H1) and other methyltransferases. In two transgenic AD mouse models (APPswe/PS1dE9 and APPswe/tauP301L/PS1tm1Mpm), we assessed ETP69 effects on cerebral H3 methylation, behavior, AD-like pathology, synaptic integrity, and proteomic profiles.