Abstract
Alzheimer’s disease (AD), probably caused by abnormal accumulation of β-amyloid (Aβ) and aberrant phosphorylation of tau, is the most common cause of dementia among older people. Generation of patient-specific neurons by induced pluripotent stem cell (iPSC) technology facilitates exploration of the disease features in live human neurons from AD patients. In this study, we generated iPSCs from two familial AD patients carrying a heterozygous D678H mutation in the APP gene (AD-iPSCs). The neurons derived from our AD-iPSCs demonstrated aberrant accumulation of intracellular and secreted Aβ42 and Aβ40, reduction of serine 9 phosphorylation in glycogen synthase kinase 3β (GSK3β) hyperphosphorylation of threonine 181 and serine 396 in tau protein, impaired neurite outgrowth, downregulation of synaptophysin, and increased caspase 1 activity. The comparison between neurons derived from a sibling pair of wild-type and mutated iPSCs successfully recapitulated these AD phenotypes. Treatment with indole compound NC009-1 (3-((1H-Indole-3-yl)methyl)-4-(2-nitrophenyl)but-3-en-2-one), a potential Aβ aggregation reducer, normalized the Aβ levels and GSK3β and tau phosphorylation, attenuated caspase 1 activity, and improved neurite outgrowth in AD-iPSC-derived neurons. Thus, APP D678H iPSCs-derived neurons recapitulate the cellular characteristics relevant to AD and enable exploration of the underlying pathogenesis and therapeutic strategies for AD.
Highlights
Alzheimer’s disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss
We established an AD-induced pluripotent stem cell (iPSC) model that recapitulated the crucial phenotypes of AD from two familial AD patients carrying the Amyloid peptide precursor protein (APP) D678H mutation
In addition to aberrant accumulation of Aβ and tau phosphorylation, this AD-iPSC model demonstrated important features of impaired neurite outgrowth accompanied with SYP downregulation and high caspase 1 activity
Summary
Alzheimer’s disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. The pathological hallmarks of AD include senile plaques and neurofibrillary tangles. Senile plaques are composed of Aβ peptide, a fragment of the amyloid peptide. Any treatment to prevent or slow the rate of AD progression is still lacking. One of the critical limitations for AD research is the paucity of live neurons from patients for a mechanistic approach and drug discovery. Establishment of the human-induced pluripotent stem cells (iPSCs) model has facilitated the generation of patient-specific neurons to study patient-specific characteristics in AD [8].
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