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iPSC‐derived engineered cerebral organoids (enCORs) as in vitro models of tauopathy
Author(s) -
Lovejoy Christopher E.J.,
Alatza Argyro,
Arber Charles,
Bradshaw Teisha,
Lashley Tammaryn,
Hardy John,
Wray Selina
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039816
Subject(s) - neurogenesis , organoid , notch signaling pathway , biology , hippocampal formation , psen1 , microbiology and biotechnology , induced pluripotent stem cell , neural stem cell , neuroscience , amyloid precursor protein , alzheimer's disease , stem cell , genetics , pathology , embryonic stem cell , signal transduction , medicine , gene , disease
Background Familial Alzheimer’s disease (fAD) is caused by mutations in PSEN1 , PSEN2 and APP . PSEN1 forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Ab generation. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis. Method We generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APP mutation lines and 7 PSEN1 mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers. Result We describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1 during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. We see describe robust, quantifiable neurogenesis in post‐mortem tissue using b‐III‐tubulin immunohistochemistry. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue. Conclusion These findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1 , but not APP , alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification.