Investigating Selective Neuronal Vulnerability in Alzheimer’s and Parkinson’s Disease with Induced Pluripotent Stem Cells and Pre‐formed Fibrils

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AbstractBackgroundAlzheimer’s and Parkinson’s disease feature progressive neurodegeneration associated with the accumulation of protein aggregates in a remarkably regionally selective manner. The cortical neurons that are relatively vulnerable in Alzheimer’s Disease (AD) are only affected late in Parkinson’s Disease (PD), whereas midbrain dopaminergic neurons exhibit striking vulnerability in PD, but are relatively spared in AD. Rodent and human post mortem studies have posited a role for cell autonomous mechanisms such as autophagy or calcium buffering deficits driving this, but having a live human cell model that can replicate the phenomenon of selective neuronal vulnerability can help to better determine common and contrasting disease mechanisms and identify therapeutic targets.MethodHere, we used induced pluripotent stem cell (iPSC) derived neurons as they offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD‐related presenilin‐1 mutations (n = 3), PD‐related leucine rich repeat kinase 2 mutations (G2019S n = 3, R1441C n = 3), and isogenic corrected (n = 3) and healthy controls (n = 4) have been differentiated into both cortical neurons and midbrain dopaminergic neurons to enable comparison of vulnerability phenotypes in different neuronal subtypes from the same patient.ResultAD cortical neurons insulted with alpha‐synuclein pre‐formed fibrils (PFFs) have impaired neurite outgrowth, reduced synaptic density, and extensive aggregate formation. Meanwhile, PFF insulted PD cortical neurons exhibit normal neurite outgrowth and relatively little aggregation, whereas PD dopamine neurons readily produce aggregates.ConclusionThese preliminary results show relative vulnerability of AD and resilience of PD cortical neurons to alpha synuclein aggregates for the first time. This suggests the selective vulnerability to proteinopathy exhibited in these diseases may be replicated by the iPSC neuronal model, and additionally supports the notion that cell intrinsic factors may partly determine this vulnerability.