Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death

Molecular Neurodegeneration

John A Kessler²  Richard J Miller¹  Liuliu Pan²  Abdelhak Belmadani¹  Bula J Bhattacharyya¹  Lishu Duan² 

[1] Molecular Pharmacology and Biological Chemistry, University’s Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA;Departments of Neurology, Northwestern University’s Feinberg School of Medicine, Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA

关键词: Calcium abnormalities;    Glutamate excitotoxicity;    Aβ rise;    Aβ42/40 ratio;    Basal forebrain cholinergic neurons;    Human induced pluripotent stem cells;    Alzheimer’s disease;   

Others  :  861831
DOI  :  10.1186/1750-1326-9-3

 received in 2013-07-04, accepted in 2014-01-03,  发布年份 2014

【 摘 要 】

An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a constant feature of Alzheimer’s 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 Aβ42/Aβ40 ratios. AD-E3/E4 neurons also exhibited altered responses to treatment with γ-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.

【 授权许可】

   
2014 Duan et al.; licensee BioMed Central Ltd.

【 图 表 】

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