Editors' ChoiceAlzheimer’s Disease

Modeling Alzheimer’s disease in mice with human neurons

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Science Translational Medicine  15 Mar 2017:
Vol. 9, Issue 381, eaam9867
DOI: 10.1126/scitranslmed.aam9867

Abstract

Human neurons transplanted into a mouse model for Alzheimer’s disease show human-specific vulnerability to β-amyloid plaques and may help to identify new therapeutic targets.

Obtaining valid models of human disorders is one of the biggest challenges of translational research. Alzheimer’s disease (AD) researchers know this issue very well and for decades have been devoting lots of resources to establishing models for studying this devastating neurodegenerative disorder. Since the generation of the first AD transgenic mouse model in the mid-'90s, there has been an outburst of new transgenic animals, each showing AD-related phenotypes but failing to recapitulate crucial aspects of the disease, such as the extensive neuronal cell loss observed in postmortem tissue of AD patients. Recently, human-based models have been explored and shown to be useful for studying molecular changes contributing to the formation of β-amyloid plaques and neurofibrillary tangles. However, these failed to recapitulate the neurodegenerative aspect of the disease, probably due to the lack of neuroinflammatory components in vitro.

Now, Espuny-Camacho and colleagues describe a human/mouse hybrid model system that recapitulates most aspects of the pathological events observed in AD and identifies human-specific molecules possibly contributing to the severity of the disease in humans. The researchers grafted human induced pluripotent stem cell–derived neurons into the brain of an AD murine model. In this context, originally healthy human neurons develop key features of AD neurons, including neuritic dystrophy and alterations of synaptic markers. Importantly, grafted human but not mouse neurons started degenerating in AD mice, with substantial human cell loss six months after the transplantation. Thus, even when they are exposed to the same cues, human and mouse neurons respond differently to AD-related pathological changes, suggesting an innate vulnerability of human neurons. This evidence reveals how critical it is to use human neurons in AD studies.

Although using this chimeric model for large-scale drug screens may be not feasible, this system could be applied to test the utility of a few specific drugs. Most importantly, the human/mouse chimeric model allows an assessment of vulnerability of patient-derived neuronal cells, giving the possibility of analyzing nonfamilial cases of AD. Last, as explored by Espuny-Camacho and colleagues, this model could be applied to identify human-specific factors contributing to AD onset. Such factors could be used as biomarkers and/or therapeutic targets.

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