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

Molecular Neurodegeneration

Chun-Li Zhang¹  Meng-Lu Liu¹  Shuaipeng Ma¹  Tong Zang¹ 

[1] Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, 75390, Dallas, TX, USA;Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, 75390, Dallas, TX, USA;

关键词: Alzheimer’s disease;    Aging;    BFCNs;    Reprogramming;    Fibroblasts;    Nucleocytoplasmic transport;    TAU hyperphosphorylation;   

DOI  :  10.1186/s13024-020-00411-6

来源: Springer

【 摘 要 】

BackgroundAlzheimer’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.MethodsWe 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.ResultsWe 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.ConclusionsAging-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.

【 授权许可】

CC BY