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Alzheimer disease

CRISPR activation reveals hidden γ-secretase defect in fibroblasts from patients with familial AD

Nature Reviews Neurology volume 14, page 3 (2018)Cite this article

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Patient skin fibroblasts can offer an easily accessible cell model of disease, but key genes relevant to neurological disorders are often expressed at insufficient levels to study the pathomechanisms of such disorders in this system. In a new study, researchers increased expression of APP and/or BACE1 via CRISPR gene activation in fibroblasts from patients with familial Alzheimer disease (AD) and from healthy individuals. CRISPR activation revealed a defect in γ-secretase processing of amyloid precursor protein (APP) in fibroblasts from patients with familial AD, resulting in increased levels of amyloid-β42 (Aβ42), whereas no such defects were detectable in non-modified fibroblasts from the same patients. The results suggest that increasing the expression levels of APP or BACE1 to reflect those observed in cultured neurons produces a more disease-relevant fibroblast model that is quicker and easier to establish than induced pluripotent stem cell systems.

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References

  1. Inoue, K. et al. CRISPR transcriptional activation analysis unmasks an occult γ-secretase processivity defect in familial Alzheimer's disease skin fibroblasts. Cell Rep. 21, 1727–1736 (2017)

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  1. Charlotte Ridler
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Ridler, C. CRISPR activation reveals hidden γ-secretase defect in fibroblasts from patients with familial AD. Nat Rev Neurol 14, 3 (2018). https://doi.org/10.1038/nrneurol.2017.172

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