H3K9me3 inhibition reverses Alzheimer′s progression by restoring synaptic and immune proteostasis across the brain–retina axis

Epigenetic dysregulation is increasingly linked to ageing and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains uncharacterized. We quantified the repressive histone mark H3K9me3 in post-mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. In both tissues, H3K9me3 increased in early stages and further in AD dementia, strongly associating with cognitive status and neuropathological burden. To assess causality, we inhibited the H3K9 methyltransferase SUV39H1 in APPswe/PS1dE9 and APPswe/tauP301L/PS1tm1Mpm mouse models. SUV39H1 inhibition lowered H3K9me3, mitigated AD-like pathology, restored synaptic integrity, and improved cognitive and visual performance. Proteomics revealed that H3K9me3 derepression reestablished retinal and brain proteostasis and promoted neuroprotection through immunomodulatory pathways and BDNF/VGF–granin signalling. These findings identify H3K9me3 as shared epigenetic driver of AD-related dysfunction, highlight H3K9me3 reduction as therapeutic strategy, and position the retina as an accessible extension of the brain for epigenetic studies.