title: Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death.
abstract: 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.
authors.affiliation: Departments of Neurology, Northwestern University's Feinberg School of Medicine, Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA. LishuDuan2011@u.northwestern.edu.
authors.forename: Lishu
authors.initials: L
authors.lastname: Duan
authors.forename: Bula J
authors.initials: BJ
authors.lastname: Bhattacharyya
authors.forename: Abdelhak
authors.initials: A
authors.lastname: Belmadani
authors.forename: Liuliu
authors.initials: L
authors.lastname: Pan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.forename: John A
authors.initials: JA
authors.lastname: Kessler
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D015153:Blotting, Western; D018929:Cell Culture Techniques / Q000379:methods*; D016923:Cell Death; D002478:Cells, Cultured; D059329:Cholinergic Neurons; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D016548:Prosencephalon / Q000166:cytology
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4