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

Liuliu Pan,Abdelhak Belmadani,Lishu Duan,John A Kessler,Bula J Bhattacharyya,Richard J Miller

doi:10.1186/1750-1326-9-3

Liuliu Pan, Abdelhak Belmadani

Open Access

https://doi.org/10.1186/1750-1326-9-3

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Journal: Molecular Neurodegeneration	Publication Date: Jan 1, 2014
Citations: 192	License type: cc-by

Affiliation: Northwestern University

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.

Highlights

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disorder that typically occurs in the elderly
We focused on sporadic AD with an ApoE3/E4 genotype and found that basal forebrain cholinergic neurons (BFCNs) derived from such patients display biochemical abnormalities associated with the disease and are more susceptible to both glutamate- and calcium- mediated cell death
Some approaches for the differentiation of human embryonic stem cells (hESCs) and Induced pluripotent stem cells (iPSCs) are inefficient for generating BFCNs [31], and we used an approach that included retinoic acid followed by specific factors to induce a forebrain phenotype (SHH and Fibroblast Growth Factor 8 (FGF8)) and nuclefection with two transcription factors (Lhx8 and Gbx1) that specify the BFCNs phenotype

Summary

Introduction

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disorder that typically occurs in the elderly. The majority of AD cases are sporadic without any known genetic mutations. Polymorphism in the Apolipoprotein E (ApoE) gene is a strong risk factor for AD. Compared to individuals with an ApoE3/E3 genotype, the presence of one copy of the E4 allele increases AD risk by 2 to 3 fold, and two copies of E4 increases risk up to 12 fold [1,2]. The etiology of AD is poorly understood, but there are consistent pathologic features of diseased brains including senile plaques composed of β-amyloid [3,4], and neurofibrillary tangles formed by hyperphosphorylated tau [5]. Β-amyloid plaques are comprised of aggregated, extracellularly deposited Aβ peptides.

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