Single-cell analysis reveals neuroprotective histone deacetylase inhibitor pathways

Area of Science:

• Neuroscience
• Genomics
• Pharmacology

Background:

• Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaques, tau tangles, and neuroinflammation, leading to cognitive decline.
• Current disease-modifying therapies for AD are limited, necessitating novel therapeutic strategies.
• This research integrates advanced omics techniques to discover new drug candidates for AD.

Purpose of the Study:

• To identify repurposable drugs for Alzheimer's disease (AD) using computational drug repurposing.
• To investigate the therapeutic potential of identified drug candidates in preclinical models.
• To elucidate the molecular mechanisms underlying the neuroprotective effects of candidate drugs.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were employed for cell-type-specific analysis of AD cortical tissues.
• Computational drug repurposing identified Trichostatin-A (TSA) as a top candidate.
• In vitro validation using human induced pluripotent stem cell (iPSC)-derived neurons exposed to Aβ oligomers confirmed TSA's efficacy.

Main Results:

• Trichostatin-A (TSA) demonstrated significant neuroprotection against Aβ toxicity and preserved synaptic integrity in neuronal models.
• Disrupted-In-Schizophrenia 1 (DISC1) was found to be upregulated in TSA-treated neurons and specific AD-related cell populations.
• DISC1 expression correlated with protective microglial subtypes, suggesting its role in AD pathogenesis and response to therapy.

Conclusions:

• DISC1 emerges as a convergent therapeutic target for Alzheimer's disease (AD).
• TSA's neuroprotective effects are mediated by DISC1 through pathways involving GSK3β, mitochondrial transport, and synaptic plasticity.
• This study provides a mechanistic basis for developing novel AD therapeutics targeting the DISC1 pathway.