Reduced SV2A and GABAA receptor levels in the brains of type 2 diabetic rats revealed by [18F]SDM-8 and [18F]flumazenil PET

Abstract

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_A) 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 [¹⁸F]SDM-8 (SV2A), [¹⁸F]flumazenil (GABA_A receptor), [¹⁸F]florbetapir (amyloid-β), [¹⁸F]PM-PBB3 (tau), and [¹⁸F]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 [¹⁸F]SDM-8 uptake and cortical and hippocampal [¹⁸F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [¹⁸F]florbetapir and [¹⁸F]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_A 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_A receptor levels in the brains of aged T2DM ZDF rats.

Keywords: Amyloid-beta; GABA(A) receptor; SV2A; Tau; Type 2 diabetes mellitus.