INVESTIGATING THE ROLE OF POLY (ADP) RIBOSE POLYMERASE-1 IN ALZHEIMER'S DISEASE AND FRONTOTEMPORAL DEMENTIA

Common stress pathways govern disease progression in neurodegenerative disorders. Poly (ADP) ribose (PAR) Polymerase-1 (PARP-1) is a central molecule that activates following extrinsic or intrinsic neuronal injury in models of cerebral ischemia and Parkinson's disease. Reactive oxygen species (ROS) accumulation is an early sign of stress observed after a cellular insult, and PARP-1 activation is a direct result of DNA damage caused by accumulating ROS. Chronically activated PARP-1 is reported in multiple neurological disorders yet its impact in engendering neurodegeneration is underappreciated. The goal of my thesis was to evaluate the impact of PARP-1 deletion against two major neuropathologies, namely- amyloid-β plaques and aggregated tau causing neurofibrillary tangles. We hypothesized that PARP-1 uniquely drives disease progression in both these neuropathologies. In the first half of my thesis, I studied the impact of PARP-1 deletion in amyloid-β (Aβ) models. PARP-1 is activated in a DNA damage-dependent fashion in oligomeric Aβ1-42 treated primary cortical neurons. In aged familial Alzheimer’s disease (FAD) containing 5 familial mutations, 5XFAD mice, loss of PARP-1 significantly improved disease mice memory along with increased neuronal survival, decreased extracellular plaque, and large attrition in glial cell numbers. Upon further investigation, we found that PARP-1 directly impacts amyloid-β generation. In the second half of my thesis, we evaluated the relationship between PARP-1 and tau. Tau-PFF-treated primary cortical neuron cultures showed increased PAR activation and tau phosphorylation. Using a genetic model of Frontotemporal dementia (FTD) with tau pathology- MAPT-P301S mice model, we observed similar patterns of protection upon PARP-1 deletion as observed in the 5XFAD mice – decreased tau pathology, increased neuronal survival, improved memory, and decreased gliosis. Mechanistically, we found that PAR directly interacts with tau causing it to further aggregate and this interaction takes place in the microtubule-binding domain of tau. In summary, we found that robust activation of PARP-1 is crucial in mediating both amyloid plaque and tau pathology