Protein Arginine Methyltransferases in Alzheimer's disease

Project Summary Alzheimer's disease is one of the most common and progressive genetic neurodegenerative disorders in the US with more than 5 million people currently living with Alzheimer's disease with risk factors often associated with age and sex. Women are more likely to develop a rapid progression of Alzheimer's disease, than men when predictive factors such as obesity, lifespan, and enhanced stroke severity are considered. Protein arginine methyltransferases are a prevalent posttranslational modification that can occur in both the nucleus and cytoplasm and are thought to be involved in many disease processes. This emerging and difficult area of inquiry has limited investigations into the neurovascular system, brain emergent networks, with only indirect applications related to neurological diseases, where the functional role of protein arginine methyltransferases as they relate to brain metabolism, circulation, functional learning and memory are understudied. We seek to investigate protein arginine methyltransferase 4 as an important age and sex(female)-related brain regulatory element to delay neuronal senescence. We propose that protein arginine methyltransferase 4 is enhanced in aged 3xTg-AD female mice v. their young and male counterparts. This leads to the disruption of neurovascular coupling, blood brain barrier integrity, and functional learning and memory. Our central hypothesis is inhibition of protein arginine methyltransferase 4 can enhance neurovascular coupling, maintain blood-brain- barrier integrity, and attenuate learning/memory deficits in aged 3xTg-AD female mice. We describe protein arginine methyltransferase 4 modulation as a therapeutic potential against Alzheimer's disease and other vascular cognitive impairment disorders.