Neuroinflammation induced by amyloid-forming pancreatic amylin: Rationale for a mechanistic hypothesis.

Amylin is a systemic neuroendocrine hormone co-expressed and co-secreted with insulin by pancreatic ß-cells. In persons with thype-2 diabetes, amylin forms pancreatic amyloid triggering inflammasome and interleukin-1ß signaling and inducing ß-cell apoptosis. Here, we summarize recent progress in understanding the potential link between amyloid-forming pancreatic amylin and Alzheimer's disease (AD). Clinical data describing amylin pathology in AD alongside mechanistic studies in animals are reviewed. Data from multiple research teams indicate higher amylin concentrations are associated with increased frequency of cognitive impairment and amylin co-aggregates with ß-amyloid in AD-type dementia. Evidence from rodent models further suggests cerebrovascular amylin accumulation as a causative factor underlying neurological deficits. Analysis of relevant literature suggests that modulating the amylin-interleukin-1ß pathway may provide an approach for counteracting neuroinflammation in AD.

Rapid, scalable assay of amylin-ß amyloid co-aggregation in brain tissue and blood.

Islet amyloid polypeptide (amylin) secreted from the pancreas crosses from the blood to the brain parenchyma and forms cerebral mixed amylin-ß amyloid (Aß) plaques in persons with Alzheimer's disease (AD). Cerebral amylin-Aß plaques are found in both sporadic and early-onset familial AD; however, the role of amylin-Aß co-aggregation in potential mechanisms underlying this association remains unknown, in part due to lack of assays for detection of these complexes. Here, we report the development of an ELISA to detect amylin-Aß hetero-oligomers in brain tissue and blood. The amylin-Aß ELISA relies on a monoclonal anti-Aß mid-domain antibody (detection) and a polyclonal anti-amylin antibody (capture) designed to recognize an epitope that is distinct from the high affinity amylin-Aß binding sites. The utility of this assay is supported by the analysis of molecular amylin-Aß codeposition in postmortem brain tissue obtained from persons with and without AD pathology. By using transgenic AD-model rats, we show that this new assay can detect circulating amylin-Aß hetero-oligomers in the blood and is sensitive to their dissociation to monomers. This is important because therapeutic strategies to block amylin-Aß co-aggregation could reduce or delay the development and progression of AD.

Aß efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.

Impairment of vascular pathways of cerebral ß-amyloid (Aß) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aß clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aß within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aß co-deposits. LRP1-mediated Aß transport across the blood-brain barrier and Aß clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aß deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aß pathology.

Type-2 Diabetes, Pancreatic Amylin, and Neuronal Metabolic Remodeling in Alzheimer's Disease.

Type-2 diabetes raises the risk for Alzheimer's disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic ß-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid ß (Aß) pathology, in both sporadic and familial Alzheimer's disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. This review summarizes recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggests nutritional and medical effects of food constituents that might prevent and/or ameliorate amylin-mediated neuronal metabolic remodeling.