amylin and amyloid
High plasma levels of amylin were associated with obesity and type 2 diabetes, as well as with other biomarkers of metabolic syndrome and cerebrovascular disease including low HDL levels, high creatinine levels, and non-linear increased levels of cholesterol and LDL (Table 2). Use the link below to share a full-text version of this article with your friends and colleagues. The ratio of Aβ1-40/Aβ1-42 was decreased with increasing quartile of amylin in the presence of ApoE4 allele (median: Q1 = 10.1; Q2 = 9.0; Q3 = 8.5 and Q4 = 7.3, p = 0.006). Amylin or Islet Amyloid Polypeptide (IAPP) A neuroendocrine hormone 37-amino acid peptide first reported in 1987 Co-localized and co-secreted with insulin from pancreatic b-cells actions as a hormone, growth factor, and modifier of behavior Deficient in diabetes Amylin InsulinHuman amylin 3 If our mouse finding indicating that peripheral amylin passes through the BBB and removes Aβ from the brain is relevant to humans, we anticipate that amylin will be positively associated with Aβ in human plasma samples. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late onset AD without clinically apparent diabetes. These results (summarized in Figure 6F) demonstrate a role of circulating aggregated amylin in early AD and suggest that restoring amylin homeostasis may reduce AD pathology. ● National Institutes of Health AG057290, AG053999, NS116058, UK ADC P30 AG028383; ● University of Kentucky Research Alliance to Reduce Diabetes‐Associated Microvascular Dysfunction; ● UK Dementia Research Institute, which receives its funding from DRI Ltd, UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK; ● Medical Research Council (award number MR/N026004/1); ● Wellcome Trust Hardy (award number 202903/Z/16/Z); ● National Institute for Health Research University College London Hospitals Biomedical Research Centre; ● BRCNIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London; ● Wake Forest Alzheimer's Disease Research Center P30 AG049638 ; ● H.L. Details on antibodies, reagents, and image analysis are included in Appendix A. Observer‐blind measurement of CSF amylin levels was performed by using amylin ELISA (EIA‐AMY; RayBiotech). Compared to the ApoE4 non-carriers, ApoE4 carriers had a slightly lower concentration of Aβ1-42 in plasma (p = 0.03) and a higher Aβ1-40/Aβ1-42 ratio (p = 0.007). Increased brain amylin concentrations were associated with greater Aβ42 levels in PS1 versus CU brains (ELISA; Figure 1C). It has been reported that injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine AD models 26 and proposed that amylin protects against AD effects in humans. As Aβ is a key element of AD pathogenesis in the brain [17], if a drug or substance like amylin or its analogs can enhance the removal of Aβ from the AD brain into the blood, it might prove an effective treatment for the disease. While no causal link between T2D and amyloid has been established, the S20G mutation in amylin is associated with early-onset T2D. To address the potential for altering AD‐related pathology/symptoms through modulation of the blood amylin level, we genetically manipulated amylin secretion in APP/PS1 and non‐APP/PS1 rats by pancreatic overexpression of human amylin (3‐fold) or amylin gene deletion. B, Plasma amylin levels in APP/PS1 rats intravenously infused with human amylin and age matched APP/PS1 control rats at baseline and after injections (, Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Alzheimer’s & Dementia: Diagnosis, Assessment and Disease Monitoring, Alzheimer’s Disease for Primary Care Physicians, I have read and accept the Wiley Online Library Terms and Conditions of Use, Future prospects and challenges for Alzheimer's disease drug development in the era of the NIA‐AA Research Framework, NIA‐AA Research Framework: toward a biological definition of Alzheimer's disease. Therefore, the co-existence of Aβ and amylin in the brain suggests the potential ability of amylin to infiltrate the brain and induce amyloid deposition in the brain [ 81 ]. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums, Glucose and endoplasmic reticulum calcium channels regulate HIF‐1beta via presenilin in pancreatic beta‐cells, Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease, Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults, Molecular interaction between type 2 diabetes and Alzheimer's disease through cross‐seeding of protein misfolding, Amyloid‐beta and islet amyloid pathologies link Alzheimer's disease and type 2 diabetes in a transgenic model, Alzheimer's & Dementia: Translational Research & Clinical Interventions. Amylin is a short peptide of 37 amino acids produced and secreted by the pancreas. Amylin has dose-dependent effects on amyloid formation in the presence of region of interest (ROI) 3. Greater pathological processes in brains of aged APP/PS1/HIP versus APP/PS1 rats were associated with circulating aggregated amylin (Figure S5), and this was also the case in plasma from aged HIP versus WT rats.7, 15, 18 To assess the impact of circulating aggregated human amylin (amyloid forming) on early AD pathological processes, young APP/PS1 rats (age 7 months), studied before the development of Aβ pathology (which occurs at age ≈16 months), were injected intravenously with pre‐aggregated human amylin (Figure 6A; the schematic schedule of the treatment). No, Is the Subject Area "Blood-brain barrier" applicable to this article? Frozen and formalin fixed brain tissues were processed as previously described.3, 7 Brain amylin and Aβ concentrations were measured using the enzyme‐linked immunosorbent assay (ELISA) for amylin (EZHA‐52K, Millipore) and Aβ42 (KHB3441, Thermo Fisher). Next, we tested amylin–Aβ interaction in aged APP/PS1/HIP and APP/PS1 littermates using IHC co‐staining with anti‐amylin and anti‐Aβ antibodies in brain slices (Figure 4A‐E). ; methodology: J.H., H.Z., T.L., G.J.B., L.B.G., R.G., J.B., AESG, A.J.M., E.L.A., S.D., and F.D. Variables with skewed distributions (plasma amylin, Aβ1-42, Aβ1-40, and Aβ1-40/Aβ1-42 ratio) were presented as median (25th, 75th percentiles) and compared using Wilcoxon rank sum test for ApoE4 subgroups or using Kruskal-Wallis test across quartiles [24]. A nonsignificant increased brain accumulation of amylin was also identified in APP versus CU brains (P = 0.09; Figure 1B), which is similar to the tendency for higher Aβ42 in this group (P = 0.07; Figure 1C). No, Is the Subject Area "Mouse models" applicable to this article? Citation: Qiu WQ, Wallack M, Dean M, Liebson E, Mwamburi M, Zhu H (2014) Association between Amylin and Amyloid-β Peptides in Plasma in the Context of Apolipoprotein E4 Allele. Briefly, plates were coated with 2G3 (anti-Aβ40) and 21F12 (anti-Aβ42) antibodies overnight at 4°C. The presence of ApoE4 may attenuate amylin's capacity to remove Aβ, especially Aβ1-40, from the AD brain. We tested the association of brain amylin accumulation with blood‐brain barrier (BBB) leak by assessing the brain uptake of immunoglobulins (IgG). Note that when using cell cultures, insulin and Aβ encounter each other in the cell media and a significantly positive relationship between insulin and Aβ is observed [3]–[5]. Administering exogenous amylin, either peripherally or intracerebroventricularly, results in reduced appetite and food intake [8]. Amylin‐Aβ cross‐seeding was identified in AD brains. Brains of APP/PS1 rats intravenously infused with human amylin also showed neuronal amylin deposition (Figure 6D), consistent with our findings in APP/PS1/HIP rats (Figure 4E) and human fAD brains (Figure 1F‐G), and higher soluble amylin and Aβ levels by western blot analysis of brain homogenates (Figure 6E and Figure S11 in supporting information). The average CSF levels of both amylin and Aβ42 are associated with the cognitive status (Figure 2A‐B). A recent study found an accumulation of amylin amyloid in the cerebrovascular system in the AD brain, resulting in impaired vascular functioning [6]. Amylin Structure, Aggregation, and Pancreatic β Cell Toxicity Sharadrao Maruti Patil, PhD University of Connecticut, 2015 In most type 2 diabetes patients, amyloid plaques have been found juxtaposed with Interpretation of results: Early AD processes may affect the central regulation of pancreatic amylin leading to abnormal circulating amylin and amylin–Aβ cross‐seeding in the brain. Our recent study using AD mouse models demonstrated that i.p. A clinical trial of pramlintide in AD, an off-label use, may be warranted. Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America, Higher plasma levels of amylin (combined human and rat amylin) in APP/PS1/HIP versus APP/PS1 rats are associated with lower CSF Aβ levels (Figure 4I) and more cerebral plaques (Figure 4F). BBB dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Aβ from brain are all thought to contribute to AD pathogenesis [15]. For all analyses, the two-sided significance level of 0.05 was used. The extent of Aβ pathology was similar in APP/PS1 and APP/PS1/AKO rats (Figure 5J). Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p.) https://doi.org/10.1371/journal.pone.0088063.g001, https://doi.org/10.1371/journal.pone.0088063.t005. 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). The concentration of creatinine was positively associated with both log10 of plasma Aβ1-40 and log10 of plasma Aβ1-42. Study design and study time points are described in Figure 3A‐C. In MCI, however, CSF amylin and Aβ42 levels were inversely correlated, with lower Aβ42 levels being associated with higher amylin levels (Figure 2D). This positive association between amylin and Aβ1-42 in plasma was found regardless of the ApoE genotype. BBB dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Aβ from the brain are all thought to contribute to AD pathogenesis [15]. The CSF amylin–Aβ42 relationship needs to be further tested in a larger sample with longitudinal characterization of the cohort. 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]. After adding kidney function as assessed by concentration of creatinine, log10 of amylin was still associated with either log10 of plasma Aβ1-42 (β = +0.150, SE = 0.024, P<0.0001) or log10 of plasma Aβ1-40 (β = +0.031, SE = 0.016, P = 0.05) (Model II), but the relationships were attenuated. Amylin has been shown to have a vasorelaxant effect [37] that may result in enhanced removal of Aβ from the brain. Neuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer’s disease (AD) pathology. 85‐23, revised 2011) and was approved by the Institutional Animal Care and Use Committees at University of Kentucky. AD Centers at the University of Kentucky, University of Washington (USA), Wake Forest University (USA), and University of Gothenburg (Sweden) provided the CSF samples for this study (98 diseased and 117 control samples). Marshal Folatein who had the vision to establish the NAME study more than a decade ago, Dr. Xiaoyan Sun who measured plasma amylin and Aβ, and the NAME study staff and the Boston homecare agencies for their hard work and acquisition of subjects. IHC co‐staining with anti‐amylin and anti‐Aβ antibodies in fAD brain sections detected distinct amylin and Aβ plaques and mixed amylin–Aβ plaques (Figure 1F‐M). There were no differences in lipid profiles between the two ApoE4 subgroups. Both formalin fixed and frozen tissue was available for 14 brains. ... the biggest obstacles in creating synthetic amylin is that it contains “ physicochemical properties ” that can form “ amyloid fibers ” which are known as a potential threat to beta-cells in people with type 2 diabetes. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. In turn, low amylin levels are more strongly associated with the late stages of amyloid disorders [ 40 ]. Forming Plaques. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Databases from the International Genomics of Alzheimer's Project (IGAP; n = 17,008 AD cases and n = 13,154 controls) and Healthy Exosomes (HEX; n = 331 AD cases and n = 468 controls) were used to test the association of common and rare amylin gene variants with the risk for AD. Our results demonstrated the opposite and are consistent with data showing that intracerebroventricular human amylin administration in murine AD models promotes robust amylin–Aβ cross‐seeding, accelerating AD pathology;28 and pancreatic expression of amyloid‐forming human amylin in murine AD mice exacerbate cerebral amyloid burden through cumulative diabetogenic effects of the coexpressed human amylin and Aβ.29. Those with Mini-Mental State Examination (MMSE) ≤10 or verbal IQ<75 were not eligible to continue in the study. 1) co-production/co-secretion, 2) competitive degradation/clearance, or 3) one peptide moving another to the same location. Islet amyloid formation contributes to β -cell dysfunction and death in the disease and to the failure of islet transplants.