期刊
MOLECULAR NEURODEGENERATION
卷 9, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1750-1326-9-3
关键词
Alzheimers disease; Human induced pluripotent stem cells; Basal forebrain cholinergic neurons; A beta 42/40 ratio; A beta rise; Glutamate excitotoxicity; Calcium abnormalities
资金
- NIH [R01 NS 20778, R01 NS 20013]
An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a constant feature of Alzheimers disease (AD) and is associated with deficits in spatial learning and memory. Induced pluripotent stem cells (iPSCs) derived from patients with AD as well as from normal controls could be efficiently differentiated into neurons with characteristics of BFCNs. We used BFCNs derived from iPSCs to model sporadic AD with a focus on patients with ApoE3/E4 genotypes (AD-E3/E4). BFCNs derived from AD-E3/E4 patients showed typical AD biochemical features evidenced by increased A beta 42/A beta 40 ratios. AD-E3/E4 neurons also exhibited altered responses to treatment with gamma-secretase inhibitors compared to control BFCNs or neurons derived from patients with familial AD. BFCNs from patients with AD-E3/E4 also exhibited increased vulnerability to glutamate-mediated cell death which correlated with increased intracellular free calcium upon glutamate exposure. The ability to generate BFCNs with an AD phenotype is a significant step both for understanding disease mechanisms and for facilitating screening for agents that promote synaptic integrity and neuronal survival.
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