Abstract
BackgroundType 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.MethodsWe 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 PSEN2N141I (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 PSEN2N141I mutation.ResultsWe report herein that wildtype, PSEN2N141I 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 PSEN2N141I on calcium flux, which could be prevented by chronic exposure of BFCNs to insulin.ConclusionsOur studies indicate that the familial AD mutation PSEN2N141I 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.
Highlights
Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, the exact nature of the molecular pathology of T2D-associated CI remains obscure
Chronic insulin treatment of basal forebrain cholinergic neurons (BFCN) of all genotypes led to a reduction in the Aβ42/40 ratio
A previously reported CRISPR/Cas9-correctable effect of PSEN2N141I on calcium flux could be corrected by chronic exposure of BFCNs to physiologically stimulatory concentrations of insulin
Summary
Type 2 diabetes (T2D) is a recognized risk factor for the development of cognitive impairment (CI) and/or dementia, 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). Type 2 diabetes (T2D) is associated with an increased risk for dementia in the setting of hyperinsulinemia and peripheral insulin resistance [15, 30]. There is as yet no consensus on whether the most important cause of dementia in the setting of T2D is related to Alzheimer’s disease (AD), vascular cognitive impairment and dementia (VCID) or some novel form of cognitive impairment with a predilection for a shared pathogenesis with T2D [13, 22, 26]. There is substantial interest in the repurposing of intranasal insulin as a means of improving brain insulin signaling and thereby the cognitive function of both healthy individuals [4] and AD patients [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
