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Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of the ?-amyloid peptides and intracellular neurofibrillary tangles and associates with progressive declines in memory and cognition. Several genes play important roles and regulate enzymes that produce a pathological accumulation of ?-amyloid in the brain, such as gamma secretase (?-secretase). Induced pluripotent stem cells from patients with Alzheimer's disease with different underlying genetic mechanisms may help model different phenotypes of Alzheimer's disease and facilitate personalized drug screening platforms for the identification of small molecules. We also discuss recent developments by ?-secretase inhibitors and modulators in the treatment of AD. In addition, small-molecule drugs isolated from Chinese herbal medicines have been shown effective in treating Alzheimer's disease. We propose a mechanism of small-molecule drugs in treating Alzheimer's disease. Combining therapy with different small-molecule drugs may increase the chance of symptomatic treatment. A customized strategy tailored to individuals and in combination with therapy may be a more suitable treatment option for Alzheimer's disease in the future.

SUBMITTER: Wuli W

PROVIDER: S-EPMC7072986 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer's Disease.

Wuli Wei W Tsai Sheng-Tzung ST Chiou Tzyy-Wen TW Harn Horng-Jyh HJ

International journal of molecular sciences 20200216 4

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of the β-amyloid peptides and intracellular neurofibrillary tangles and associates with progressive declines in memory and cognition. Several genes play important roles and regulate enzymes that produce a pathological accumulation of β-amyloid in the brain, such as gamma secretase (γ-secretase). Induced pluripotent stem cells from patients with Alzheimer's disease with different underlying genetic mechanisms may ...[more]

PMID: 32079110

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Project description:Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-? precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-?(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3? (aGSK-3?). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with ?-secretase inhibitors, but not ?-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3? levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-?, in GSK-3? activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.

Dataset Information

Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer's Disease.

Publications

Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer's Disease.

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