Abstract
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.
Highlights
Alzheimer’s disease (AD) is an adult-onset mental disorder with aging as a major risk factor
Our preliminary results further indicate that human induced BFCNs (hiBFCNs) from sporadic AD patients exhibit time-dependent TAU hyperphosphorylation and impairment in nucleocytoplasmic transport. hiBFCNs may be useful for understanding the molecular mechanisms and discovering novel therapeutics for age-dependent progressive AD
Rapid and efficient generation of hiBFCNs from adult human skin fibroblasts We previously showed that human skin fibroblasts can be directly converted into cholinergic neurons without passing through a progenitor stage [18]
Summary
Alzheimer’s disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. And progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of human patients with Alzheimer’s disease (AD) [2, 3]. Neurons derived from ESCs or iPSCs are young and do not exhibit aging-associated features [9, 14,15,16,17] These young neurons are advantageous in understanding neural development and for transplantationbased therapies [4, 5, 7, 11, 12]. Human induced BFCNs (hiBFCNs) from adult skin fibroblasts have not been reported
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