Single‐cell analysis reveals neuroprotective histone deacetylase inhibitor pathways

Abstract INTRODUCTION Alzheimer's disease (AD) involves β‐amyloid (Aβ) accumulation, tau pathology, and neuroinflammation, driving cognitive decline. Despite extensive research, disease‐modifying therapies remain elusive. We integrated single‐cell RNA sequencing (scRNA‐seq), spatial transcriptomics, and in vitro validation to identify repurposable drugs for AD 1 . METHODS Computational drug repurposing was performed using cell‐type‐specific analysis of scRNA‐seq datasets from AD cortical regions. Trichostatin‐A (TSA) effects were validated in human induced pluripotent stem cells (iPSC) ‐derived cortical neurons exposed to Aβ oligomers. Cross‐dataset integration identified convergent therapeutic targets. RESULTS TSA emerged as the top candidate, protecting neurons from Aβ toxicity and preserving synaptic integrity. DISC1 (Disrupted‐In‐Schizophrenia 1) was uniquely upregulated across TSA‐treated neurons, AD‐associated neuronal subpopulations, and protective microglial subtypes. DISCUSSION DISC1 represents a convergent therapeutic target for AD, mediating TSA's neuroprotective effects through pathways regulating GSK3β , mitochondrial transport, and synaptic plasticity, providing a mechanistic framework for developing AD therapeutics.