CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2N141I neurons.
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2017
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Acta Neuropathologica Communications
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Abstract
Basal forebrain cholinergic neurons (BFCNs) are believed to be one of the first cell types to be affected in all forms
of AD, and their dysfunction is clinically correlated with impaired short-term memory formation and retrieval. We
present an optimized in vitro protocol to generate human BFCNs from iPSCs, using cell lines from presenilin 2
(PSEN2) mutation carriers and controls. As expected, cell lines harboring the PSEN2N141I mutation displayed an
increase in the Aβ42/40 in iPSC-derived BFCNs. Neurons derived from PSEN2N141I lines generated fewer maximum
number of spikes in response to a square depolarizing current injection. The height of the first action potential at
rheobase current injection was also significantly decreased in PSEN2N141I BFCNs. CRISPR/Cas9 correction of the
PSEN2 point mutation abolished the electrophysiological deficit, restoring both the maximal number of spikes and
spike height to the levels recorded in controls. Increased Aβ42/40 was also normalized following CRISPR/Casmediated
correction of the PSEN2N141I mutation. The genome editing data confirms the robust consistency of
mutation-related changes in Aβ42/40 ratio while also showing a PSEN2-mutation-related alteration in
electrophysiology.
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Keywords
Alzheimer’s disease, Electrophysiology, Basal forebrain, Cholinergic, Presenilin