The Alteration of Proteomic Profiles in Hippocampus of Type 2 Diabetic Mice Associated With Cognitive Impairment.

Clinical and experimental studies have demonstrated that type 2 diabetes mellitus (T2DM) affects the brain structure and function, in particular the hippocampus, leading to cognitive impairments. However, the molecular mechanisms underlying cognitive deficits induced by T2DM are not fully understood. In this study, we aimed to investigate the effects of T2DM on behavior, the proteome profile in the hippocampus, and the potential molecular pathways involved in the development of cognitive dysfunction in T2DM mice. We found that the diabetic mice exhibited cognitive impairment in the novel object location recognition test and the novel object recognition test. The proteomic analysis revealed that various molecular pathways were involved in this context. These included the upregulation of proteins in the protein synthesis and folding pathway (EIF5A, RSP24, and PPIB), endocytosis and cellular trafficking (VPS24, SNX12, and ARP2/3), cannabinoid receptor interacting (CRIP1), ubiquitination (SKP1), and oxidative stress response (NUDT3). Downregulated proteins were related to mitochondria function (ANT1), neuronal development (ELP1), protein glycosylation (RPN2), and endocytosis (VPS4). Our study shows that T2DM mice exhibit neurocognitive impairment, which is linked to the dysregulation of hippocampal proteins involved in various molecular pathways. These findings contribute to a better understanding of the pathophysiology of T2DM-related cognitive impairment and may identify molecular targets for drug development to treat T2DM-associated cognitive impairment conditions.