Purpose: Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABA) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats.
Methods: Positron emission tomography (PET) using [F]SDM-8 (SV2A), [F]flumazenil (GABA receptor), [F]florbetapir (amyloid-β), [F]PM-PBB3 (tau), and [F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats.
Results: Reduced cortical [F]SDM-8 uptake and cortical and hippocampal [F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [F]florbetapir and [F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats.
Conclusion: These findings provide in vivo evidence for regional reductions in SV2A and GABA receptor levels in the brains of aged T2DM ZDF rats.
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| http://dx.doi.org/10.1016/j.biopha.2024.116252 | DOI Listing |
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