Non-enzymatic post-translational modifications as drivers of AD pathology

PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia, and its association with type 2 diabetes is well established. However, the molecular mechanisms underlying this link are not fully understood. Hyperglycemia and dysregulated glucose metabolism have been suggested as factors contributing to the increased risk of AD. This project aims to investigate the role of glycated tau and advanced glycation end products (AGEs) in AD pathology, neurotoxicity, aggregation, and neuroinflammation. The proposed research will pursue the following aims: Aim 1: Investigate how tau proteoforms with specific saccharide modifications control aggregation and neurotoxicity. Aim 2: Expand in vitro studies to other reactive dicarbonyl species operating through a mechanism similar to glycation. Aim 3: Evaluate the effects of glycation, AGE structure, and attachment of DOPEGAL on interneuronal transmission, inflammation, and mitochondrial dysfunction/oxidative stress. These studies will use hiPSC-derived models and will be accompanied by extensive biophysical and biochemical characterizations to develop a molecular understanding of the role of non-enzymatic post-translational modifications in AD. Successful completion of these aims will enable a more precise diagnosis of AD and can potentially lead to novel therapeutic approaches based on the perturbation of non-enzymatic modifications of tau and other proteins implicated in neurodegenerative diseases. Overall, this research will provide important insights into the molecular mechanisms of AD and may lead to the development of new treatments for this devastating disease.