Thus it is possible that endogenous and synthetic amylin have similar effects on Aβ in the brain. Because amylin is the unique peptide constituent of the islet amyloid deposits that are typically observed in individuals with type 2 diabetes (21–23), it has been suggested that increased amylin … Discover a faster, simpler path to publishing in a high-quality journal. We used ELISA assay to measure amylin concentration in plasma according to the manufacture's instructions (LINCO Research, St. Charles, Missouri). The authors declare no competing interests. Subjects were asked to show all the medications they were taking, and research assistants documented the medication names according to the labels. 1) co-production/co-secretion, 2) competitive degradation/clearance, or 3) one peptide moving another to the same location. here. The plasma Aβ42 decline seen in the pre-clinical stage of AD [33], [34], indicating the formation of AD pathology. Yes Ann Neurol. Another pancreatic peptide, insulin, is much less likely than amylin to be transported into the brain via the BBB [7], [8]. High levels of Aβ in the AD brain may block amylin's ability to bind to its receptor, thus hindering normal amylin functions that are essential to the brain [10]. In general, a positive association between two peptides in a compartment in the body can occur by three mechanisms, e.g. The presence of ApoE4 may attenuate amylin's capacity to remove Aβ, especially Aβ1-40, from the AD brain. Please enable it to take advantage of the complete set of features! Contributed reagents/materials/analysis tools: WQQ MM. Fasting blood draws were conducted. Would you like email updates of new search results? Longitudinal studies are needed to confirm the causal relationship between high levels of plasma amylin and decreased Aβdeposition in the brain. Mol Psychiatry. In plasma with increasing quartile of amylin the concentrations of Aβ1-42 (p<0.0001) increased in a linear pattern; the concentrations of Aβ1-40 (p<0.0001) also increased, but in a non-linear pattern with a U shape; and the ratios of Aβ1-40/Aβ1-42 (p<0.0001) decreased in a linear pattern. No, Is the Subject Area "Diabetes mellitus" applicable to this article? While Aβ42 is a major component of AD pathology in the brain [29], Aβ40 is a component of cerebral amyloid angiopathy (CAA) [30]. injection of synthetic amylin or its analog, pramlintide, enhanced the removal of Aβ from the brain into blood (submitted and under review). 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 Recently there … Using Spearman rank correlation analysis, the study sample showed that amylin was positively and moderately associated with Aβ1-42 (r = +0.20, p<0.0001) and Aβ1-40 (r = +0.12, p<0.0001) in plasma (Table 1). These include having similar β-sheet secondary structures, binding to the same receptor, and being degraded by the same protease. R01 AG053999/AG/NIA NIH HHS/United States, R01 NS116058/NS/NINDS NIH HHS/United States, R01 AG057290/AG/NIA NIH HHS/United States, P30 AG066509/AG/NIA NIH HHS/United States, P30 AG028383/AG/NIA NIH HHS/United States, P50 AG005136/AG/NIA NIH HHS/United States, P30 AG049638/AG/NIA NIH HHS/United States, Khachaturian AS, Hayden KM, Mielke MM, et al. Is the Subject Area "Blood plasma" applicable to this article? Performed the experiments: MW HZ. ... the biggest obstacles in creating synthetic amylin is that it contains “ physicochemical properties ” that can form “ amyloid … A‐F, Representative images of immunostaining for amylin (brown) and amyloid beta (Aβ) (green) in brain tissues from 16‐month‐old APP/PS1/AKO rats (A‐C) and APP/PS1 littermates (D‐F). 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. Am J Pathol. Genetic manipulation of circulating amylin was performed in rats with and without Alzheimer's disease (AD)‐like pathology through transgenic expression of human amylin in the pancreas (red color code, A) and by deletion of the amylin gene (light blue color code, B). 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). For plasma amylin (pM/L): median  = 22.3, Q1 = 11.8, Q3 = 40.0; for Aβ1-42 (pg/ml): median  = 17.4, Q1 = 11.8, Q3 = 22.6, and for Aβ1-40 (pg/ml): median  = 133.4, Q1 = 99.5, Q3 = 172.7. https://doi.org/10.1371/journal.pone.0088063.t001. Eligibility for enrollment required that the participants spoke English, were physically able to participate in the study home visits, and had sufficient vision and hearing to read and hear the content of the neuropsychological tests. High levels of plasma Aβ40 are associated with cerebral microvascular pathology, white matter hyperintensities (WHI) and lacunar infarcts [31], [32]. A recent study found an accumulation of amylin amyloid in the cerebrovasculature of the AD brain [6]; the resulting microvascular dysfunction may interfere with amylin's ability to relax cerebrovasculature. The ApoE4 allele is associated with BBB damage [20], which likely adversely affects removal of Aβ from brain into blood. There were no differences in lipid profiles between the two ApoE4 subgroups. Diabetes mellitus and amylin and amyloid-β protein pathologies in Alzheimer’s disease AD is one of the most prevalent dementias in older people and is characterized by the progressive loss of memory and … A, Schematic…, Cerebrospinal fluid (CSF) amylin–amyloid beta…, Cerebrospinal fluid (CSF) amylin–amyloid beta (Aβ) 42 relationship in Alzheimer's disease (AD), mild…, Behavior deficits in APP/PS1 and non‐APP/PS1 rats with genetically manipulated amylin secretion. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease. It will be important to determine whether this naturally occurring peptide derived from the pancreas has any role in regulating Aβ in the brain. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. Amylin was independently associated with Aβ even after adjusting for these biomarkers of metabolic syndrome (Table 3). To measure Aβ a sandwich Aβ ELISA was used, as described previously [24]. Although the effect of ApoE4 on the relationship between amylin and Aβ is unknown, we hypothesized that ApoE4 may attenuate amylin's activity in removing Aβ, especially Aβ40, out of the brain via the BBB. Keywords: A‐C, Schematic summary of rat models generated for this study and time points of behavior and molecular analyses. The PCR products were digested with 5 units of Hha I and the fragments separated by electrophoresis on 8% polyacrylamide non-denaturing gel. There were no differences in demographic variables between the two ApoE subgroups with the exception that African Americans were more likely to be ApoE4 carriers than ApoE4 non-carriers (48% vs. 31%, p = 0.03). For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. For all analyses, the two-sided significance level of 0.05 was used. Amylin (also known as islet amyloid polypeptide) is a hormone expressed and secreted with insulin. Brain amylin–amyloid beta (Aβ) relationship…, Brain amylin–amyloid beta (Aβ) relationship in PSEN1 and APP mutation carriers. COVID-19 is an emerging, rapidly evolving situation. 8600 Rockville Pike Departments of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America, Zhu H, Wang X, Wallack M, Li H, Carreras I, Dedeoglu A, Hur JY, Zheng H, Li H, Fine R, Mwamburi M, Sun X, Kowall N, Stern RA, Qiu WQ. All enrolled subjects gave written informed consent. The time points for behavioral studies were chosen based on previous reports that amylin dyshomeostasis develops at ≈12 months of age in human amylin expressing rats. To determine whether increased or disproportionate release of amylin may explain the propensity for amyloid deposition in type 2 diabetes, we measured plasma amylin … Amylin is a protein that regulates the body's glucose levels. Methods: Discussion: Yes However, amylin accumulation leads to amyloid … FOIA It is logical to anticipate that if two molecules do not encounter each other in the same tissue regions, they generally will not compete for the same protease degradation or bind the same receptor to be cleared or influence each other, and thus will not have a positive association. Briefly, plates were coated with 2G3 (anti-Aβ40) and 21F12 (anti-Aβ42) antibodies overnight at 4°C. Arrows indicate amylin‐core Aβ plaques (CP). 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]. We found that concentrations of Aβ1-42 (P<0.0001) and Aβ1-40 (P<0.0001) increased with each quartile increase of amylin. We divided subjects into ApoE4 non-carriers (n = 834) and ApoE4 carriers (n = 258) (Table 1). We studied a group of 1092 subjects, all of whom had measurements of plasma amylin and Aβ, as well as ApoE genotyping as part of a population-based study, the Nutrition, Aging and Memory in the Elderly (NAME) study [21]. 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. Copyright: © 2014 Qiu et al. While there was no difference in age across the four amylin quartiles, average BMI (p<0.0001), kidney function as assessed by creatinine levels (p<0.0001), and the rate of diabetes (p<0.05) all increased with increasing quartile of amylin (Table 3). All homebound elders aged 60 and older at each of the four agencies were invited to participate in the study. Most subjects (67%) had high school education or above. Adding education and MMSE to the model did not change the relationships between amylin and Aβ (data not shown). Amylin, also known as islet amyloid polypeptide (IAPP), is a hormone produced mainly by the pancreatic beta cells and that gets released into the blood together with insulin [ 1 ]. Amylin and amyloid-beta peptide (Aβ), the main component of amyloid plaques and a major component of brain Alzheimer's disease (AD) pathology, share several features, including similar β-sheet secondary structures [1], binding to the same amylin receptor [2], and being degraded by the same protease insulin-degrading enzyme (IDE) [3]–[5]. All the signed consent forms have been kept and locked in the research area. 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… In the … Thus, amylin may be associated with Aβ, but the nature of their relationship remains unclear. VZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV … 2018;14(4):532‐534. 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). It is intriguing that amylin (Tables 2 and 3) and Aβ, especially Aβ1-42, were positively associated in plasma, suggesting that naturally occurring amylin may also enhance removal of Aβ from the brain. The concentration of creatinine was positively associated with both log10 of plasma Aβ1-40 and log10 of plasma Aβ1-42. Production of intracellular amyloidogenic proteins (amylin, amyloid precursor protein [APP], and amyloid-β [Aβ]) and amyloid, as well as extracellular amylin, Aβ, and amyloid, was … Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. The specific allelic fragments were: E2; E3; and E4. Bethesda, MD 20894, Copyright It is elevated in … Chronic treatment with intraperitoneal (i.p.) The pancreatic peptide amylin is best known for its role as a satiation hormone in the control of food intake and as the major component of islet amyloid deposits in the pancreatic islets of … Plasma Aβ1-42 (A and B) and Aβ1-40 (C and D) in the absence (A and C) and presence (B and D) of ApoE4 allele in quartile 1 (Q1), quartile 2 (Q2), quartile 3 (Q3) and quartile 4 (Q4) of plasma amylin are shown. Of all eligible subjects, 66% enrolled in the study, and gave informed consent [22]. Amylin works in two ways to help manage your blood sugar levels after you eat or drink calories. Sakae N, Liu CC, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y, Tachibana M, Younkin L, Kurti A, Carrasquillo MM, Zou F, Sevlever D, Bisceglio G, Gan M, Fol R, Knight P, Wang M, Han X, Fryer JD, Fitzgerald ML, Ohyagi Y, Younkin SG, Bu G, Kanekiyo T. J Neurosci. For more information about PLOS Subject Areas, click It influences blood sugar levels; when too much is secreted, risk for developing diabetes increases. Ann Neurol. Blood samples were centrifuged immediately following blood draw to isolate plasma. Thus a high Aβ40/Aβ42 ratio in plasma may be a biomarker of cerebral microvascular pathology, which is associated with high plasma Aβ40, co-existing AD pathology, which is associated with low plasma Aβ42. Limitations of our study are its cross-sectional design and lack of brain imaging. Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, United States of America, Affiliations Funding: This work was supported by grants from National Institute on Aging, AG-022476 and Ignition Award (WQQ) and BU ADC pilot grant (HZ). Accessibility These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Using a large, homebound elderly population we aimed to examine the relationship between amylin and Aβ in blood in the context of the ApoE alleles. Amylin and islet amyloid polypeptide are currently interchangeable terms for the 37 amino acid polypeptide which forms the monomeric unit of polymerized, aggregated, and beta pleated sheet structure of islet amyloid (Figures 1, 2, 3). Pramlintide, an amylin analog differing by three amino acids, is an effective and well-tolerated drug in clinical use for the treatment of diabetes [45] [46]. Eur Arch Psychiatry Clin Neurosci. Yes It is a regulatory peptide with putative function both locally in the … A recent study found an accumulation of amylin amyloid in the cerebrovascular system in the AD brain, resulting in impaired vascular functioning [6]. 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. In ApoE4 carriers, with increasing quartile of amylin, the concentrations of Aβ1-42 increased in plasma (p = 0.0004) (Figure 1B), but the relationship between amylin quartiles and Aβ1-40 in plasma was weak and presented with a U shape (Figure 1D). Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America, Affiliation Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, United States of America, Affiliation Although amylin is a peripheral peptide produced and secreted by the pancreas and Aβ occurs primarily in the brain, especially the AD brain [16], amylin does readily cross the BBB [7], [8] and thus amylin and Aβ may therefore encounter each other in the brain. It is the major protein of islet amyloid, … Yes Amylin, also known as islet amyloid polypeptide (IAPP), is a 37-amino-acid hormone that is cosecreted with insulin from the pancreatic β-cells. A, Experimental protocol for intravenous amylin infusion in rats. Subcell Biochem. Two large, prospective population studies have shown that a high plasma Aβ40/Aβ42 ratio, determined by both low Aβ42 and high Aβ40, increases the risk of AD [27], [28]. Subjects included homebound elderly clients who were enrolled in one of four homecare agencies in the Boston area between 2002 and 2007. 2018;14(4):535‐562. The high blood sugar temporarily suppresses beta cell insulin production, (a vicious circle of its own), so that little insulin is made, but amylin … Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association. This positive association between amylin and Aβ1-42 in plasma was found regardless of the ApoE genotype. Future studies are necessary to examine the concentrations of amylin and its relationship to Aβ in specific diagnostic groups. In contrast to ApoE4 non-carriers, ApoE4 carriers had a different pattern of the relationship between amylin and Aβ. No, Is the Subject Area "Ethnicities" applicable to this article? Yes No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pone.0088063. Mixed amylin and amyloid β (Aβ) deposits were occasionally observed. "Amylin helps form plaques in the brains of some AD patients, worsening the disease. Univariate and multivariate linear regression were used to examine associations between Log Amylin and Log Aβ1-42 or Log Aβ1-40 while adjusting for age, ApoE4, depression, creatinine and other confounders. Our recent study using AD mouse models demonstrated that i.p. Amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells, has binding sites in the brain possibly regulating satiety and gastric emptying. Click through the PLOS taxonomy to find articles in your field. Amylin, a 37-amino acid peptide, is cosecreted with insulin from the β-cells of the pancreatic islets in normal response to physiological stimuli. No, Is the Subject Area "Cholesterol" applicable to this article? PLOS ONE promises fair, rigorous peer review, See this image and copyright information in PMC. It is not surprising that in the same plasma samples we did not find any association between insulin and Aβ (data not shown). Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. 2015;185(3):834‐846. 2012;65:329-52. doi: 10.1007/978-94-007-5416-4_14. Since plasma amylin levels were found to be inversely associated with Aβ40/Aβ42 ratio, it is possible that higher plasma amylin is a protecting factor for the development of AD. -, Jackson K, Barisone GA, Diaz E, Lw Jin, DeCarli C, Despa F. Amylin deposition in the brain: a second amyloid in Alzheimer disease?. In contrast, the relationship between amylin and Aβ1-40 in plasma seen in ApoE4 non-carriers disappeared in the presence of ApoE4. There were no diagnoses of AD and mild cognitive impairment (MCI) for this population based study. Diabetes was defined by the use of anti-diabetic medication or fasting glucose greater than 126 mg/dl, parameters widely used in population-based studies [26]. here. Because of their skewed distributions, amylin, Aβ1-42 and Aβ1-40 were transformed to log10 for multivariate linear regression. Our recent study using two AD mouse models demonstrates another important function of amylin in the brain. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels. Amylin is a 37-amino acid peptide that is stored in pancreatic beta cells and is co-secreted with insulin . A 244 bp fragment of the apoE gene including the two polymorphic sites was amplified by PCR using a robotic Thermal Cycler (ABI 877, Perkin-Elmer/Applied Biosystems), using oligonucleotide primers F4 (5′-ACAGAATTCGCCCCGGCCTGGTACAC-3′) and F6 (5′-TAAGCTTGGCACGGCTGTCCAAGGA-3′). They appear to affect each other in complex ways. This site needs JavaScript to work properly. Cholesterol and LDL levels had a positive relationship with increasing 1st to 3rd quartile of amylin, but their levels were lower in the 4th quartile of amylin, indicating a nonlinear relationship. Amylin (LogAmylin), Aβ1-42 (Log Aβ1-42), and Aβ1-40 (Log Aβ1-40) were transformed to log10 for multivariate regression due to skewed distributions. Amylin is a short peptide of 37 amino acids produced and secreted by the pancreas. Amylin (also known as islet amyloid polypeptide or IAPP) is a protein normally produced in the beta cells of the pancreas along with insulin, as a response to high blood sugar. Although much attention has been paid to the … Subjects are divided into four quartiles based on the concentration of amylin in plasma. 2019;86(4):539‐551. Amylin is a peptide hormone whose high propensity to form amyloid in the pancreas contributes to TD2 pathology. The primary components of amyloid and fibril-forming molecules are called hIAPP (amylin and insulin). This immune drug that removes Aβ from the AD brain into blood has been shown to delay cognitive decline in those in an early stage of AD [18]. PLoS ONE 9(2): BBB dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Aβ from brain are all thought to contribute to AD pathogenesis [15]. 2017 Sep 12;9(1):74. doi: 10.1186/s13195-017-0298-y. Co-secreted with insulin, amylin accumulates over time and … In the presence of ApoE4, while the relationship between amylin and Aβ1-42 (β = +0.112, SE = 0.042, P = 0.008) remained but attenuated, the relationship between amylin and Aβ1-40 disappeared after adjusting for the confounders (Tables 1 and 5). https://doi.org/10.1371/journal.pone.0088063.g001, https://doi.org/10.1371/journal.pone.0088063.t005. Wrote the paper: WQQ MW EL. Our current human study did indeed show a positive association between naturally occurring amylin and Aβ in plasma, likely due to a mechanism similar to that seen in the mouse model. 1999;249(6):266-70. doi: 10.1007/s004060050098. Conceived and designed the experiments: WQQ HZ. It is well known that the concentration of Aβ in blood is much lower than the concentration of Aβ in the brain [16], suggesting that only a small portion of Aβ in the brain can be removed from the brain. Alzheimers Dement. It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). No, Is the Subject Area "Creatinine" applicable to this article? In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding. Recently, heterologous amyloid composed of amylin and amyloid beta (the causative agent and amyloid … Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD). von Linstow CU, Waider J, Grebing M, Metaxas A, Lesch KP, Finsen B. Alzheimers Res Ther. ApoE4 was negatively associated with plasma Aβ1-42, but not with plasma Aβ1-40 in this model. 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 average BMI was 31.6±8.6, and 37% had a history of diabetes (Table 1). McLean Hospital, Harvard Medical School, Belmont, Massachusetts, United States of America, Affiliation Subjects were divided into ApoE4 non-carriers and carriers (Table 1). Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases.
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