Association between Amylin and Amyloid-β Peptides in Plasma in the Context of Apolipoprotein E4 Allele

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.

Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics

“…The differences between the conformational properties of toxic h-IAPP oligomers defined in the present work and those recently identified for Aβ are particularly interesting, given that the two polypeptides share important features and given the growing evidence that links T2D and AD ( Yang and Song, 2013 ; Oskarsson et al, 2015 ; Ninomiya, 2014 ). Pre-fibrillar forms of h-IAPP and Aβ interact in vitro and a positive association has recently been demonstrated in plasma ( Miklossy et al, 2010 ; Qiu et al, 2014 ). Furthermore, Aβ can seed amyloid formation by h-IAPP in vitro and Aβ has been reported to form pancreatic deposits in T2D, while h-IAPP has been reported in brain plaques in AD ( O'Nuallain et al, 2004 ; Oskarsson et al, 2015 ; Miklossy et al, 2010 ).…”

Positive Association between Plasma Amylin and Cognition in a Homebound Elderly Population

“…Our recent study found that amylin was associated with Aβ in plasma. However, in the presence of ApoE4, the association between amylin and Aβ 1–40 disappeared [34]. ApoE4 may either block or attenuate amylin’s effect on blood vessels in the brain that leads to cognitive decline.…”

Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

“…A translational study using human subjects demonstrates that a single injection of pramlintide, an amylin analog, similarly induced a surge of Aβ in plasma in AD patients (Zhu et al, 2017a). Amylin and Aβ have consistently been positively associated in plasma in humans (Qiu et al, 2014), suggesting that the more amylin in blood crossing the BBB, the more Aβ moved out of the brain into the blood.…”