Determining the long term consequences of diabetes on hippocampal function
Authors: Alonaizi Mohammed , Al Sarraf Ahmad , Rao Muddanna , Kilarkaje Narayana 
Published: April 2020

Type 2 diabetes mellitus (T2DM) is the most prevalent subtype of diabetes. T2DM is a chronic metabolic disorder that is characterized by hyperglycemia, hyperinsulimia, and insulin resistance. Diabetes is a major risk factor for Alzheimer’s Disease (AD). While the cause of AD remains unknown, several risk factors have been linked to the pathogenesis of AD, including T2DM. At the cellular and molecular level, both AD and T2DM share similar mechanistic abnormalities. Changes in brain structure in insulin‐resistant diabetes occur within temporal lobe circuits that are also sensitive to aging and AD, and individuals with insulin‐resistant diabetes exhibit hippocampal atrophy. While these studies demonstrate a clear link between AD and T2DM the exact mechanisms through which T2DM contributes to cognitive decline in AD remains unexplored. As such, there is a need for further understanding the mechanisms and establish potential therapeutic targets to the T2DM‐mediated development of AD pathology. Our laboratory investigated the effects of T2DM on AD‐like pathology using the db/db mouse model of leptin receptor deficiency. This model has a mutation in the gene encoding the leptin receptor, and thus induced leptin dysfunction confers susceptibility to obesity, insulin resistance and subsequently T2DM development. Our findings demonstrate that aged db/db mice present increased microglial cell activation and proliferation in the hippocampus, a region selectively vulnerable to AD, compared to controls. We next assessed the inflammatory profile of the hippocampus of aged db/db mice compared to controls at the molecular level using a cytokine array. We found that diabetic mice have a chronic inflammatory profile. Notably, we observed elevated levels of key proinflammatory cytokines (IL‐1α and IL‐1β), as well as anti‐inflammatory cytokines (IL‐10 and IL‐13) in aged db/db mice compared to controls. Furthermore, our profiling experiments showed a decreased expression of CX3CL1, indicating a possible dysregulation of fractalkine signaling in the hippocampus. To assess hippocampal synaptic integrity in these animals we assessed the protein expression of synaptic markers in an age‐dependent manner. We showed an age‐dependent decrease in the protein levels of PSD95 and synaptophysin in the hippocampi of db/db mice. These findings demonstrate a clear link between T2DM development and neuroinflammation and synaptic dysfunction. To evaluate the functional consequence of the neuroinflammatory profile and synaptic dysfunctioon observed in the hippocampi of diabetic mice, db/db mice and lean control mice were tested on the Morris Water Maze (MWM) task. In the MWM learning and relearning session test, diabetic animals group spent significantly more time to find the platform compared to their lean counterparts. In the memory retention tests, entry latency into the platform quadrant of the T2DM mice was significantly higher, and distance traveled in the platform quadrant was significantly lower compared to controls. The findings suggest that db/db mice have impaired spatial navigation. Our data suggest that neuroinflammation is a potential mechanism through which AD pathology and cognitive dysfunction is triggered in the diabetic state.

Support or Funding Information

This work was funded by Kuwait Univerisy grant number: ZM03/16