Modeling Sporadic Alzheimer’s Disease by Efficient Direct Reprogramming of the Elderly Derived Disease Dermal Fibroblasts into Neural Stem Cells

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, neuropathologically characterized by hyperphosphorylation of tau and formation of amyloid plaques. Most AD cases are sporadic with no clear cause. Cell models play an important role in understanding the pathogenesis of sporadic AD, and the cell reprogramming and epigenetic techniques have provided new avenue to model the disorder. However, since most sporadic AD patients are late-onset, it poses a challenge to reprogram elderly somatic cells into stem cells. Here, we report that combination of overexpressing a single transcription factor, hSOX, with nine small molecules, was able to directly reprogram elderly (55–75 years of age) sporadic AD and the age-matched healthy individual dermal fibroblasts into the induced neural stem cells (iNSCs). These cells possessed the typical neural stem cell properties and were able to be further differentiated into neurons and glia in vitro and in vivo. More importantly, AD iNSC-derived neurons showed hyperphosphorylation at several sites of tau and increased release of Aβ into culture medium, indicating the replication of the major neuropathological hallmarks. Thus, we described a new technique to directly convert elderly AD dermal fibroblasts into iNSCs that may serve as a useful tool for studying the pathogenesis of sporadic AD and for drug discovery to treat the disorder.