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Open Access 01-12-2018 | Research article

iPSC-derived familial Alzheimer’s PSEN2 ^N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling

Authors: Cesar L. Moreno, Lucio Della Guardia, Valeria Shnyder, Maitane Ortiz-Virumbrales, Ilya Kruglikov, Bin Zhang, Eric E. Schadt, Rudolph E. Tanzi, Scott Noggle, Christoph Buettner, Sam Gandy

Published in: Molecular Neurodegeneration | Issue 1/2018

Abstract

Background

Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, although the exact nature of the molecular pathology of T2D-associated CI remains obscure. One link between T2D and CI might involve decreased insulin signaling in brain and/or neurons in either animal or postmortem human brains as has been reported as a feature of Alzheimer’s disease (AD). Here we asked if neuronal insulin resistance is a cell autonomous phenomenon in a familial form of AD.

Methods

We have applied a newly developed protocol for deriving human basal forebrain cholinergic neurons (BFCN) from skin fibroblasts via induced pluripotent stem cell (iPSC) technology. We generated wildtype and familial AD mutant PSEN2^N141I (presenilin 2) BFCNs and assessed if insulin signaling, insulin regulation of the major AD proteins Aβ and/or tau, and/or calcium fluxes is altered by the PSEN2^N141I mutation.

Results

We report herein that wildtype, PSEN2^N141I and CRISPR/Cas9-corrected iPSC-derived BFCNs (and their precursors) show indistinguishable insulin signaling profiles as determined by the phosphorylation of canonical insulin signaling pathway molecules. Chronic insulin treatment of BFCNs of all genotypes led to a reduction in the Aβ42/40 ratio. Unexpectedly, we found a CRISPR/Cas9-correctable effect of PSEN2^N141I on calcium flux, which could be prevented by chronic exposure of BFCNs to insulin.

Conclusions

Our studies indicate that the familial AD mutation PSEN2^N141I does not induce neuronal insulin resistance in a cell autonomous fashion. The ability of insulin to correct calcium fluxes and to lower Aβ42/40 ratio suggests that insulin acts to oppose an AD-pathophysiology. Hence, our results are consistent with a potential physiological role for insulin as a mediator of resilience by counteracting specific metabolic and molecular features of AD.

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Title: iPSC-derived familial Alzheimer’s PSEN2 N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling
Authors: Cesar L. Moreno
Lucio Della Guardia
Valeria Shnyder
Maitane Ortiz-Virumbrales
Ilya Kruglikov
Bin Zhang
Eric E. Schadt
Rudolph E. Tanzi
Scott Noggle
Christoph Buettner
Sam Gandy
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/s13024-018-0265-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

iPSC-derived familial Alzheimer’s PSEN2 ^N141I cholinergic neurons exhibit mutation-dependent molecular pathology corrected by insulin signaling

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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