Dysfunctional neuronal differentiation links type-2 diabetes and Alzheimer's disease

Craig, Tim; Targett, Imogen; Crompton, Lucy

Abstract

Introduction:
Type 2 diabetes mellitus (T2DM) is one of the most significant risk factors for late-onset Alzheimer’s Disease (LOAD), associated with a nearly 2-fold increase in risk, although the reasons for this are not fully understood. Several recent studies have reported dysregulated hippocampal neurogenesis in AD patients and mouse models, and there is evidence that this also occurs in T2DM, suggesting this could explain the connection between T2DM and AD. This study aims to investigate how chronic exposure to fatty acids, which are raised in T2DM and obesity, affect neuronal differentiation, serving here as a model of neurogenesis.
Methods:
Human SH-SY5Y neuroblastoma cells were subjected to a 10-day differentiation protocol involving retinoic acid and brain-derived neurotrophic factor, which resulted in robust differentiation with abundant neuronal processes in control cells. To mimic conditions in Type-2 Diabetes, cells were exposed to a physiologically relevant dose of oleic or palmitic acid (OA or PA; monosaturated and saturated fatty acids respectively which are raised T2DM and AD) throughout differentiation. Morphology, differentiation, and signalling markers were evaluated by Western blotting and confocal microscopy at different timepoints during this process.
Approach for Statistical Analysis:
All data is presented as mean +/- SEM. Statistical tests used were either 1- or 2-way ANOVA with Bonferroni’s post-hoc tests for comparing pairs of mean. * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001.
Results and conclusions:
Chronic PA treatment caused a profound dysregulation of differentiation, including decreased expression of pre- and postsynaptic markers (synaptophysin and PSD-95). PA also disrupted key signalling pathways, including Akt, CDK5/p35 and GSK3β. Importantly, none of these effects occurred if the cells were exposed to the same concentration of PA post-differentiation. All of these effects were absent or less severe in OA-exposed cells. Furthermore, PA-exposed cells displayed severe insulin resistance and a dysregulation of CREB phosphorylation, although there was no increase in either Aβ production or Tau phosphorylation. Overall, our data suggest that differentiating neurones are uniquely vulnerable to levels of PA observed in T2DM and obese patients, and that this exposure triggers a dysfunction in neurogenesis. We conclude that this dysregulation may represent an early event in the link between T2DM and AD, preceding both amyloid and tau pathology. We therefore hypothesise that chronic saturated fatty acid exposure is one of the mechanistic links between T2DM and AD.

• Presentation Conference Type: Presentation / Talk
• Conference Name: BNA (British Neuroscience Association) International Festival of Neuroscience
• Start Date: Apr 27, 2025
• End Date: Apr 30, 2025
• Acceptance Date: Feb 12, 2025
• Deposit Date: May 12, 2025
• Publicly Available Date: May 13, 2025
• Peer Reviewed: Peer Reviewed
• Public URL: https://uwe-repository.worktribe.com/output/14416152