Abstract
Amylin, a pancreatic peptide that readily crosses the blood brain barrier (BBB), and amyloid-beta peptide (Aβ), the main component of amyloid plaques and a major component of Alzheimer's disease (AD) pathology in the brain, share several features. These include having similar β-sheet secondary structures, binding to the same receptor, and being degraded by the same protease. Thus, amylin may be associated with Aβ, but the nature of their relationship remains unclear. In this study, we used human samples to study the relationship between plasma amylin and Aβ in the context of the apolipoprotein E alleles (ApoE). We found that concentrations of Aβ1-42 (P<0.0001) and Aβ1-40 (P<0.0001) increased with each quartile increase of amylin. Using multivariate regression analysis, the study sample showed that plasma amylin was associated with Aβ1-42 (β = +0.149, SE = 0.025, P<0.0001) and Aβ1-40 (β = +0.034, SE = 0.016, P = 0.04) as an outcome after adjusting for age, gender, ethnicity, ApoE4, BMI, diabetes, stroke, kidney function and lipid profile. This positive association between amylin and Aβ1-42 in plasma was found regardless of the ApoE genotype. In contrast, the relationship between amylin and Aβ1-40 in plasma seen in ApoE4 non-carriers disappeared in the presence of ApoE4. Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p.) injection of synthetic amylin enhances the removal of Aβ from the brain into blood, thus resulting in increased blood levels of both amylin and Aβ. The positive association between amylin and Aβ, especially Aβ1-42, in human blood samples is probably relevant to the findings in the AD mouse models. The presence of ApoE4 may attenuate amylin's capacity to remove Aβ, especially Aβ1-40, from the AD brain.
Highlights
Amylin is a short peptide of 37 amino acids produced and secreted by the pancreas
Study Population and Recruitment We studied a group of 1092 subjects, all of whom had measurements of plasma amylin and amyloid-beta peptide (Ab), as well as ApoE genotyping as part of a population-based study, the Nutrition, Aging and Memory in the Elderly (NAME) study [21]
Our recent study using Alzheimer’s disease (AD) mouse models demonstrated that i.p. injection of synthetic amylin or its analog, pramlintide, enhanced the removal of Ab from the brain into blood
Summary
Amylin and amyloid-beta peptide (Ab), the main component of amyloid plaques and a major component of brain Alzheimer’s disease (AD) pathology, share several features, including similar b-sheet secondary structures [1], binding to the same amylin receptor [2], and being degraded by the same protease insulin-degrading enzyme (IDE) [3,4,5] They appear to affect each other in complex ways. A recent study found an accumulation of amylin amyloid in the cerebrovascular system in the AD brain, resulting in impaired vascular functioning [6]. Amylin readily penetrates the blood brain barrier (BBB) [7,8] and mediates important brain functions including inhibiting appetite thereby improving glucose metabolism[9,10], relaxing cerebrovascular structure [11,12], and, in all likelihood, enhancing neural regeneration [13]. High levels of Ab in the AD brain may block amylin’s ability to bind to its receptor, hindering normal amylin functions that are essential to the brain [10]
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