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

Abstract

Impairment of vascular pathways of cerebral β-amyloid (Aβ) 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 Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ 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 Aβ pathology.

The association between renal accumulation of pancreatic amyloid-forming amylin and renal hypoxia

“…Amylin is a 37 amino acid long pancreatic hormone and co-secreted with insulin from beta cells ( 15 – 18 ). Studies from our lab and from other labs showed amylin have novel function in renal function and path-physiology and also in other organs ( 19 – 24 ). A recent study from our lab showed that red blood cell (RBC)-capillary interaction is altered by prediabetic hypersecretion of amylin that could be a potential contributing factor to renal hypoxia in diabetic kidney injury ( 19 ).…”

Recent Developments in the Design and Fabrication of Electrochemical Biosensors Using Functional Materials and Molecules

“…Hence, these chemicals and other waste products need to be treated and eliminated or converted to other non-hazardous products; in order to achieve this, they need to be identified and quantified [ 12 , 13 , 14 ]. Therefore, it is indispensable to detect and quantify various significant analytes, from biofluids to environmental samples, in order to prevent or eliminate various diseases and disorders [ 15 , 16 ].…”

Plasma IAPP-Autoantibody Levels in Alzheimer’s Disease Patients Are Affected by APOE4 Status

“…Immunohistological stainings show that IAPP often co-localizes with Aβ42 in plaques and Aβ40 in vessel walls [ 14 , 15 ]. Furthermore, a recent study using human and animal models has demonstrated that pancreas-derived IAPP accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, further inducing cerebrovascular inflammation [ 18 ]. IAPP (and its non-amyloidogenic analogue pramlintide) also plays a crucial role in Aβ brain-to-blood clearance [ 18 , 19 , 20 ].…”

“…Furthermore, a recent study using human and animal models has demonstrated that pancreas-derived IAPP accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, further inducing cerebrovascular inflammation [ 18 ]. IAPP (and its non-amyloidogenic analogue pramlintide) also plays a crucial role in Aβ brain-to-blood clearance [ 18 , 19 , 20 ]. Interestingly, this clearance, especially of Aβ40, is attenuated in the presence of APOE4 [ 21 ], leading to an exacerbated IAPP deposition and vascular pathology [ 16 ].…”