Single-cell analysis reveals neuroprotective histone deacetylase inhibitor pathways.

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 AD1.

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.