Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer’s disease

Shuaipeng Ma, Tong Zang, Meng Lu Liu, Chun Li Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Alzheimer’s disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of AD. An aging-relevant cell model of BFCNs will critically help understand AD and identify potential therapeutics. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. However, human induced BFCNs (hiBFCNs) have yet to be achieved. Methods: We examined a reprogramming procedure for the generation of aging-relevant hiBFCNs through virus-mediated expression of fate-determining transcription factors. Skin fibroblasts were obtained from healthy young persons, healthy adults and sporadic AD patients. Properties of the induced neurons were examined by immunocytochemistry, qRT-PCR, western blotting, and electrophysiology. Results: We established a protocol for efficient generation of hiBFCNs from adult human skin fibroblasts. They show electrophysiological properties of mature neurons and express BFCN-specific markers, such as CHAT, p75NTR, ISL1, and VACHT. As a proof-of-concept, our preliminary results further reveal that hiBFCNs from sporadic AD patients exhibit time-dependent TAU hyperphosphorylation in the soma and dysfunctional nucleocytoplasmic transport activities. Conclusions: Aging-relevant BFCNs can be directly reprogrammed from human skin fibroblasts of healthy adults and sporadic AD patients. They show promises as an aging-relevant cell model for understanding AD pathology and may be employed for therapeutics identification for AD.

Original languageEnglish (US)
Article number61
JournalMolecular neurodegeneration
Volume15
Issue number1
DOIs
StatePublished - Dec 1 2020

Keywords

  • Aging
  • Alzheimer’s disease
  • BFCNs
  • Fibroblasts
  • Nucleocytoplasmic transport
  • Reprogramming
  • TAU hyperphosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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