Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease.
Zhong-Ming ZhaoAndi LiuCitu CituNitesh EnduruXian ChenAstrid ManuelTirthankar SinhaDamian GorskiBrisa FernandesMeifang YuPaul E SchulzLukas M SimonClaudio SotoPublished in: Research square (2024)
Sporadic early-onset Alzheimer's disease (sEOAD) represents a significant but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis -regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.
Keyphrases
- late onset
- early onset
- transcription factor
- gene expression
- induced apoptosis
- genome wide
- cell cycle arrest
- resting state
- prefrontal cortex
- single cell
- functional connectivity
- neuropathic pain
- dna methylation
- cognitive decline
- endoplasmic reticulum stress
- cerebral ischemia
- oxidative stress
- spinal cord
- spinal cord injury
- dna damage
- inflammatory response
- cell proliferation
- blood brain barrier
- mild cognitive impairment
- risk assessment
- subarachnoid hemorrhage
- heat shock protein