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

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

doi:10.1186/1750-1326-9-3

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

134 Scopus citations

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.

Original language	English (US)
Article number	3
Journal	Molecular neurodegeneration
Volume	9
Issue number	1
DOIs	https://doi.org/10.1186/1750-1326-9-3
State	Published - Jan 8 2014

Funding

We thank Dr. Kitamura from University of Tokyo for kindly providing us the pMXs vector and Plat-E virus packaging cell line. Ljuba Lyass from Stem Cell Core Facility of Northwestern University for help with cell culturing. Paul Mehl and Jeffery Nelson from Flow Cytometry Core Facility of Northwestern University for help with fac-sorting. And we thank Chian-yu Peng, Lixin Kan and Dilyan Dryanovski from Northwestern University for suggestions and inputs with experiments. This research if supported by NIH grants: R01 NS 20778 and R01 NS 20013.

Keywords

Alzheimer's disease
Aβ rise
Aβ42/40 ratio
Basal forebrain cholinergic neurons
Calcium abnormalities
Glutamate excitotoxicity
Human induced pluripotent stem cells

ASJC Scopus subject areas

Clinical Neurology
Cellular and Molecular Neuroscience
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/1750-1326-9-3

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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.",

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note = "Funding Information: We thank Dr. Kitamura from University of Tokyo for kindly providing us the pMXs vector and Plat-E virus packaging cell line. Ljuba Lyass from Stem Cell Core Facility of Northwestern University for help with cell culturing. Paul Mehl and Jeffery Nelson from Flow Cytometry Core Facility of Northwestern University for help with fac-sorting. And we thank Chian-yu Peng, Lixin Kan and Dilyan Dryanovski from Northwestern University for suggestions and inputs with experiments. This research if supported by NIH grants: R01 NS 20778 and R01 NS 20013.",

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doi = "10.1186/1750-1326-9-3",

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AU - Pan, Liuliu

AU - Miller, Richard J.

AU - Kessler, John A.

N1 - Funding Information: We thank Dr. Kitamura from University of Tokyo for kindly providing us the pMXs vector and Plat-E virus packaging cell line. Ljuba Lyass from Stem Cell Core Facility of Northwestern University for help with cell culturing. Paul Mehl and Jeffery Nelson from Flow Cytometry Core Facility of Northwestern University for help with fac-sorting. And we thank Chian-yu Peng, Lixin Kan and Dilyan Dryanovski from Northwestern University for suggestions and inputs with experiments. This research if supported by NIH grants: R01 NS 20778 and R01 NS 20013.

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N2 - 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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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