# Single‐cell analysis reveals neuroprotective histone deacetylase inhibitor pathways

## TL;DR

Single-cell analysis identified trichostatin-A as a promising drug candidate for Alzheimer's disease, with DISC1 as a key gene in its protective effects.

## Contribution

A novel multi-modal framework integrating computational and experimental validation to identify repurposable drugs and therapeutic targets for Alzheimer's disease.

## Key findings

- Trichostatin-A (TSA) protects neurons from amyloid-β toxicity and preserves synaptic integrity.
- DISC1 is uniquely upregulated across TSA-treated neurons, AD-associated neuronal subpopulations, and protective microglial subtypes.
- DISC1 mediates TSA's neuroprotective effects through pathways regulating GSK3β, mitochondrial transport, and synaptic plasticity.

## Abstract

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.

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.

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.

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.

Single‐cell analysis identified trichostatin‐A as the top drug candidate for Alzheimer's disease (AD).DISC1 emerged as the only gene upregulated across all experimental conditions.Trichostatin‐A (TSA) protected human neurons from amyloid‐β toxicity and preserved synapses.DISC1 upregulation by TSA persisted even in the presence of amyloid‐β pathology.Novel multi‐modal framework integrates computational and experimental validation.

Single‐cell analysis identified trichostatin‐A as the top drug candidate for Alzheimer's disease (AD).

DISC1 emerged as the only gene upregulated across all experimental conditions.

Trichostatin‐A (TSA) protected human neurons from amyloid‐β toxicity and preserved synapses.

DISC1 upregulation by TSA persisted even in the presence of amyloid‐β pathology.

Novel multi‐modal framework integrates computational and experimental validation.