Abstract: Raman, Piontkivska & Fleming

Smooth muscle O-GlcNAcylation, cognitive function and AD pathology in diabetes

Drs. Priya Raman (Biomedical Sciences, NEOMED), Helen Piontkivska (Biological Sciences, Kent State University) and Sheila Fleming (Pharmaceutical Sciences, NEOMED)

Alzheimer’s disease-related dementia (ADRD) is an increasing burden for millions of people worldwide. Growing literature supports the notion that dysregulated VSMC function is a putative player in AD-related pathology and neurodegeneration. Type 2 diabetes (T2D) negatively impacts cerebrovascular function and increases the risk of developing ADRD. Hyperglycemia, a hallmark feature of T2D, increases O-linked  N-acetylglucosamine (O-GlcNAc) transferase (OGT) signaling, a key regulator of protein O-GlcNAcylation. Increased O-GlcNAcylation, a ubiquitous posttranslational modification, correlates with adverse vascular remodeling and vascular dysfunction in T2D. However, it is unknown whether increased cerebrovascular O-GlcNAcylation contributes to cognitive dysfunction and AD pathology in T2D. Guided by our preliminary data, this study provides a unique platform to determine whether loss of VSMC-specific OGT-mediated O-GlcNAcylation blocks VSMC de-differentiation to diseased phenotypes, inhibiting cerebrovascular dysfunction, cognitive decline, and AD-related pathology in diabetes. Using a diet-induced murine model of T2D with VSMC-restricted Ogt deletion combined with VSMC-specific reporter gene expression, we will pursue cellular, molecular, and transcriptomics studies coupled with behavioral testing to measure cognitive, neuropsychiatric, and sensorimotor behavior.  Overall, the proposed studies will significantly advance our molecular understanding of how diabetes contributes to cognitive dysfunction and AD pathology, with a focus on the regulatory role of cerebrovascular OGT and O-GlcNAcylation, paving the way for the discovery of novel therapies to treat ADRD in diabetes.