Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

• DOI: 10.1101/2023.09.18.558276
• Publication Date: 2023-09-19T04:30:21Z
• Authors: Daniel C. Xu; Hanna Sas-Nowosie...; Greg Donahue; Hua Huang; Naemeh Pourshafie; Charly R. Good; Shelley L. Berger
• Keywords: Amyloid; 0303 health sciences; Amyloid beta-Peptides; Research; Acetylation; tau Proteins; Histones; Amyloid beta-Protein Precursor; 03 medical and health sciences; Alzheimer Disease; Humans; Neurology. Diseases of the nervous system; RC346-429

Abstract Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques tau neurofibrillary tangles in the brain. Dysregulation epigenetic histone modifications may lead to expression transcriptional programs that play role either protecting against disease genesis or worsening pathology. One such modification, acetylation H3 lysine residue 27 (H3K27ac), primarily localized genomic enhancer regions promotes active gene transcription. We previously discovered H3K27ac be more abundant AD patient brain tissue compared brains age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial patients with an precursor protein (APP) duplication (APP Dup neurons) as model study functional effect lowering CBP/P300 enzymes catalyze at enhancers. found homeostatic amyloid-reducing genes were upregulated APP neurons non- demented lowered reduce H3K27ac, which led decreased numerous these genes, along increased extracellular secretion toxic amyloid-β species, Aβ(1-42). Our findings suggest epigenomic acetylation, including drives compensatory genetic response AD-associated insults, specifically those resulting duplication, thus mitigating pathology neurons.