Project Summary Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain that affects 35 million people in the world and 5.5 in the USA. AD is the most common form of dementia accounting for up to 56% of cases years after diagnosis. Limited therapies are available for AD and they do not delay or halt the progression of disease and thus new treatments are urgently needed. AD is characterized by the accumulation of cerebral plaques composed of amyloid-β (Aβ), which is believed to be an early pathogenic event. Most cases of AD are sporadic and develop after the age of 65 years. Recent studies have indicated an overall impairment in Aβ clearance, rather than Aβ overproduction to be critical in AD. One of the most common observations in AD, present in up to 98% of AD patients, is the presence of cerebral amyloid angiopathy (CAA). A recent study has demonstrated that vascular smooth muscle cells (VSMCs) in the brain are capable of mediating local clearance of Aβ. CAA is also a major trigger of intracranial hemorrhage a feature of cerebrovascular disease (CVD). This is significant since there is a large body of literature demonstrating a link between CVD and AD and its correlation with dementia. Despite the importance of the vasculature in AD, the link between Aβ clearance through VSMCs and increased CVD leading to dementia is not fully understood. NUDT21, also known as cleavage factor 25 (CFIm25), is an RNA binding protein that when depleted leads to alternative polyadenylation (APA) and global 3'UTR shortening. Our research on NUDT21 has revealed that depletion of NUDT21 is present in the brains of patients with AD and leads to alterations in protein transport and processing pathways in vascular smooth muscle cells (VSMCs). Our overall hypothesis is that loss of cerebral vascular smooth muscle NUDT21 disrupts Aβ clearance and predisposes the brain to CVD. This will be tested in the following Specific Aims: 1- Evaluate the role of NUDT21 loss and 3'UTR landscape in AD; 2- Determine whether NUDT21 depletion promotes CAA and 3- Assess whether NUDT21 depletion exacerbates cerebrovascular disease (CVD). Successful completion of these experiments is expected to reveal new insights into the pathogenesis of AD and AD related dementias (ADRD). Specifically, this proposal aims to uncover novel pathways related to vascular Aβ clearance and predisposition to CVD linked by APA induced by loss of NUDT1. These concepts have not been fully explored in AD thus; this proposal has the potential to stimulate additional activity leading to progress on AD and ADRD.