Role of Oligomerized Amylin in Vascular Injury and Alzheimer's Disease

We have recently found that amylin, a pancreatic hormone that is co-secreted with insulin and has cytotoxic properties similar to beta-amyloid (Abeta), accumulates in brain blood vessels and parenchyma of individuals suffering from dementia. Given the pathological effect of amylin deposition in the development of type-2 diabetes and cardiovascular disease, the discovery of brain amylin amyloid deposition has at least four paradigm-shifting implications. First, we suggest that the vascular amylin amyloid is a previously unknown cause of cerebral amyloid angiopathy resulting from elevated blood amylin, which is common in obesity and pre-diabetes. So, lowering amylin incorporation in brain blood vessels should reduce cerebral amyloid angiopathy. Second, the presence of independent amylin amyloid (and mixed amylin-Abeta deposits) in brain blood vessels could also offer an explanation for the longstanding observation that diabetes increases the risk of cognitive decline. Moreover, we found neurologic deficits and neuroinflammation in an animal model of brain amylin deposition, which demonstrates that amylin accumulation in the brain negatively affect the neurovascular unit independent of Abeta pathology. Consequently, controlling amylin homeostasis should promote neurovascular health. Third, identifying amylin deposits in brain blood vessels and brain parenchyma of Alzheimer’s disease (AD) patients without clinical evidence of diabetes suggests that amylin deposition may be an additional pathway of brain insulin resistance and injury. So, understanding how amylin interacts with the Abeta pathology in non-diabetic AD patients is highly relevant as it could afford research opportunities for novel treatments of AD. Fourth, we propose that the oligomerized amylin and mixed amylin-Abeta oligomers circulating in plasma or/and cerebrospinal fluid may be novel potential biomarkers of cognitive decline. Therefore, assessment of these biomarkers, alone or in combination with other markers, may enable predictions on the onset of clinical symptoms, disease progression and responsiveness to treatment. Here, we propose to test these ideas. The AD Center of the University of Kentucky will provide brain tissue, plasma and cerebrospinal fluid from well clinically documented patients, which will help clarifying whether brain amylin accumulation is associated with cognitive impairment. Studies on human tissues will be complemented with interventions and functional analyses in a unique combination of “humanized” rodent models that enables a mechanistic dissection of the brain amylin pathology. The successful completion of this project offers the potential to refining diagnosis and tailoring specific therapies to modify/ delay/ prevent cerebrovascular injury and cognitive decline in aging, pre-diabetes and diabetes.