High glucose‐mediated VPS26a down‐regulation dysregulates neuronal amyloid precursor protein processing and tau phosphorylation

Background and Purpose The relationship between hyperglycaemia‐induced retromer dysfunction impairing intracellular trafficking and Alzheimer's disease (AD) remains unclear, although diabetes mellitus (DM) is considered a risk factor for AD. Here, we investigated the effects of high glucose on...

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Published in:British journal of pharmacology 2022-08, Vol.179 (15), p.3934-3950
Main Authors: Chae, Chang Woo, Choi, Gee Euhn, Jung, Young Hyun, Lim, Jae Ryong, Cho, Ji Hyeon, Yoon, Jee Hyeon, Han, Ho Jae
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amyloid precursor protein
APP
Cathepsin D
Cell differentiation
Cognitive ability
Diabetes
Diabetes mellitus
Endosomes
Glucose
Golgi apparatus
Hyperglycemia
Mannose
Neural stem cells
Neurodegenerative diseases
Phosphorylation
Pluripotency
Protein transport
Proteins
retromer
Risk factors
Streptozocin
tau
Tau protein
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Summary:Background and Purpose The relationship between hyperglycaemia‐induced retromer dysfunction impairing intracellular trafficking and Alzheimer's disease (AD) remains unclear, although diabetes mellitus (DM) is considered a risk factor for AD. Here, we investigated the effects of high glucose on the retromer and defined the dysregulation of mechanisms of amyloid precursor protein (APP) processing and tau phosphorylation. Experimental Approach We used human induced‐pluripotent stem cell‐derived neuronal differentiated cells and SH‐SY5Ys exposed to high glucose to identify the underlying mechanisms. Streptozotocin‐induced diabetic mice were used to elucidate whether the retromer contributes to the AD‐like pathology. Key Results We found that vacuolar protein sorting‐associated protein 26a (VPS26a) was decreased in the hippocampus of diabetic mice and high glucose‐treated human neuronal cells. High glucose down‐regulated VPS26a through ROS/NF‐κB/DNA methyltransferase1‐mediated promoter hypermethylation. VPS26a recovery blocked retention of APP and cation‐independent mannose‐6‐phosphate receptor in endosomes and promoted transport to the trans‐Golgi, which decreased Aβ levels, and improved cathepsin D activity, reducing p‐tau levels, respectively. Retromer enhancement ameliorated synaptic deficits, astrocyte over‐activation, and cognitive impairment in diabetic mice. Conclusion and Implications In conclusion, VPS26a is a promising candidate for the inhibition of DM‐associated AD pathogenesis by modulating APP processing and tau phosphorylation.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.15836