A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome

Cultured cerebral cortex neurons generated from human Down syndrome induced pluripotent stem cells rapidly develop Alzheimer’s disease pathologies. A Window into the Alzheimer’s Disease Brain Alzheimer’s disease (AD) is a major global health problem for which there are no disease-modifying treatments. A human cellular model of AD would enable detailed functional studies of AD pathogenesis and would provide a simple way to screen for new drugs. An effective cellular model would use the appropriate cell type (in this case, glutamatergic projection neurons of the human cerebral cortex), would develop accurate pathology, and would do so in a reproducible manner over a time scale short enough for practical use. A pressing general question, however, is whether neurological diseases that take decades to become manifest in humans could be successfully modeled over a reasonable time scale in cultured cells. Shi et al. tackle this challenge using cerebral cortex neurons generated from stem cells derived from people with Down syndrome, who have a genetic predisposition to developing AD at a young age. They demonstrate that the cultured cortical neurons develop the two characteristic pathological hallmarks of AD in a few months, suggesting that complex neurodegenerative diseases that take decades to manifest in human patients can be modeled reliably in cultured neurons over a period of months. Individuals with Down syndrome (caused by trisomy of chromosome 21) have a very high risk of developing AD because they carry an extra copy of a major AD-associated gene, which encodes amyloid precursor protein (APP). First, Shi et al. made cortical neurons from induced pluripotent stem cells from Down syndrome patients. They then showed that these neurons in just a few months develop the two characteristic pathological hallmarks of AD: aggregates of amyloid peptides generated by misprocessing of APP and neurofibrillary tangles of hyperphosphorylated tau protein. These pathologies were developed by cortical neurons derived from not only Down syndrome induced pluripotent stem cells but also Down syndrome embryonic stem cells. This finding demonstrated that these pathologies were reproducible in cortical neurons derived from different sources and that their formation was not influenced by the cellular reprogramming strategy used to derive induced pluripotent stem cells from adult fibroblasts. The buildup of pathological amyloid aggregates in the cultured human cortical neurons could be blocked by a drug called γ-secretase, which is being tested in clinical trials for treating AD. The new work of Shi et al. suggests that human cortical neurons derived from stem cells from Down syndrome patients will be useful for screening new candidate drugs and for developing new disease intervention strategies for treating AD. Human cellular models of Alzheimer’s disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset AD, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein, resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a γ-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell–derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.