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Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of AD. An aging-relevant cell model of BFCNs will critically help understand AD and identify potential therapeutics. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. However, human induced BFCNs (hiBFCNs) have yet to be achieved. METHODS:We examined a reprogramming procedure for the generation of aging-relevant hiBFCNs through virus-mediated expression of fate-determining transcription factors. Skin fibroblasts were obtained from healthy young persons, healthy adults and sporadic AD patients. Properties of the induced neurons were examined by immunocytochemistry, qRT-PCR, western blotting, and electrophysiology. RESULTS:We established a protocol for efficient generation of hiBFCNs from adult human skin fibroblasts. They show electrophysiological properties of mature neurons and express BFCN-specific markers, such as CHAT, p75NTR, ISL1, and VACHT. As a proof-of-concept, our preliminary results further reveal that hiBFCNs from sporadic AD patients exhibit time-dependent TAU hyperphosphorylation in the soma and dysfunctional nucleocytoplasmic transport activities. CONCLUSIONS:Aging-relevant BFCNs can be directly reprogrammed from human skin fibroblasts of healthy adults and sporadic AD patients. They show promises as an aging-relevant cell model for understanding AD pathology and may be employed for therapeutics identification for AD.

SUBMITTER: Ma S

PROVIDER: S-EPMC7579825 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease.

Ma Shuaipeng S Zang Tong T Liu Meng-Lu ML Zhang Chun-Li CL

Molecular neurodegeneration 20201021 1

<h4>Background</h4>Alzheimer's disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of AD. An aging-relevant cell model of BFCNs will critically help understand AD and identify potential therapeutics. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. ...[more]

PMID: 33087140

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Project description:Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary financial and emotional burdens (Apostolova, 2016). Studies of pathogenesis are essential for defining critical molecular and cellular events and for discovering therapies to prevent or mitigate their effects. Through studies of neuropathology, genetic and cellular, and molecular biology recent decades have provided many important insights. Several hypotheses have been suggested. Documentation in the 1980s of selective loss of cholinergic neurons of the basal forebrain, followed by clinical improvement in those treated with inhibitors of acetylycholinesterase, supported the "cholinergic hypothesis of age-related cognitive dysfunction" (Bartus et al., 1982). A second hypothesis, prompted by the selective loss of cholinergic neurons and the discovery of central nervous system (CNS) neurotrophic factors, including nerve growth factor (NGF), prompted the "deficient neurotrophic hypothesis" (Chen et al., 2018). The most persuasive hypothesis, the amyloid cascade hypothesis first proposed more than 25 years ago (Selkoe and Hardy, 2016), is supported by a wealth of observations. Genetic studies were exceptionally important, pointing to increased dose of the gene for the amyloid precursor protein (APP) in Down syndrome (DS) and a familial AD (FAD) due to duplication of APP and to mutations in APP and in the genes for Presenilin 1 and 2 (PSEN1, 2), which encode the γ-secretase enzyme that processes APP (Dorszewska et al., 2016). The "tau hypothesis" noted the prominence of tau-related pathology and its correlation with dementia (Kametani and Hasegawa, 2018). Recent interest in induction of microglial activation in the AD brain, as well as other manifestations of inflammation, supports the "inflammatory hypothesis" (Mcgeer et al., 2016). We place these findings in the context of the selective, but by no means unique, involvement of BFCNs and their trophic dependence on NGF signaling and speculate as to how pathogenesis in these neurons is initiated, amplified and ultimately results in their dysfunction and death. In so doing we attempt to show how the different hypotheses for AD may interact and reinforce one another. Finally, we address current attempts to prevent and/or treat AD in light of advances in understanding pathogenetic mechanisms and suggest that studies in the DS population may provide unique insights into AD pathogenesis and treatment.

Dataset Information

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease.

Publications

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease.

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