Amylin works in two ways to help manage your blood sugar levels after you eat or drink calories. Given the effectiveness of the amylin class of peptides in reducing amyloid pathology in the brain in the preclinical study and the relationship between amylin and Aβ in the context of ApoE allele seen in this human study, pramlintide may have potential as a treatment in AD. In general, a positive association between two peptides in a compartment in the body can occur by three mechanisms, e.g. Department of Public Health and Family Medicine, Tufts University, Boston, Massachusetts, United States of America. This would lead to a positive relationship between these two peptides in blood. However, the authors' patent application does not alter the authors' adherence to PLOS ONE policies on sharing data and material. Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America, The high blood sugar temporarily suppresses beta cell insulin production, (a vicious circle of its own), so that little insulin is made, but amylin … Performed the experiments: MW HZ. PLoS ONE 9(2): 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; amyloid; familial Alzheimer's disease; islet amyloid polypeptide; sporadic Alzheimer's disease. Amylin's major role in the brain is to reduce food intake thereby controlling body weight and regulating glucose metabolism [44]. 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. Brain amylin–amyloid beta (Aβ) relationship…, Brain amylin–amyloid beta (Aβ) relationship in PSEN1 and APP mutation carriers. -, Jack CR Jr, Bennett DA, Blennow K, et al. Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, United States of America, Affiliation Since increased amylin was more associated with Aβ1-42 than with Aβ1-40, the ratio of Aβ1-40/Aβ1-42 was decreased with increasing quartile of amylin in the absence (median: Q1 = 8.7; Q2 = 7.7; Q3 = 7.0 and Q4 = 6.6, p = 0.0001). 2015;185(3):834‐846. 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. The average age (mean ± SD) of this study sample was 75.0±8.0 years old, and 76% were female. Amylin levels were inversely associated with the Aβ1-40/Aβ1-42 ratio in plasma (Table 2 and Figure 1). 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]. 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. BBB dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Aβ from the brain are all thought to contribute to AD pathogenesis [15]. It is not surprising that in the same plasma samples we did not find any association between insulin and Aβ (data not shown). Ann Neurol. 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). It is a regulatory peptide with putative function both locally in the … Amyloid deposits within the islet of the pancreas have been known for a century. Clipboard, Search History, and several other advanced features are temporarily unavailable. All homebound elders aged 60 and older at each of the four agencies were invited to participate in the study. NIA‐AA Research Framework: toward a biological definition of Alzheimer's disease. 2018;14(4):532‐534. The use of solanezumab is an example of this treatment strategy. Since some ApoE4 carriers do not develop AD even at a great age [38], other factors, such as amylin, may interact with ApoE4 to influence AD development. Subjects were divided into ApoE4 non-carriers and carriers (Table 1). There were no diagnoses of AD and mild cognitive impairment (MCI) for this population based study. See this image and copyright information in PMC. 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. Future prospects and challenges for Alzheimer's disease drug development in the era of the NIA‐AA Research Framework. De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. 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. Box plots were used to illustrate the median concentration with 25% (Q1) and 75% (Q3) range of plasma Aβ. 2018;14(4):535‐562. -, Oskarsson ME, Paulsson JF, Schultz SW, Ingelsson M, Westermark P, Westermark GT. The PCR products were digested with 5 units of Hha I and the fragments separated by electrophoresis on 8% polyacrylamide non-denaturing gel. 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. Yes Bethesda, MD 20894, Copyright Its major component is the normal beta-cell secretory product amylin, or islet amyloid polypeptide (IAPP). 2012;65:329-52. doi: 10.1007/978-94-007-5416-4_14. 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. injection of synthetic amylin or its analog, pramlintide, enhanced the removal of Aβ from the brain into blood (submitted and under review). In the absence of ApoE4, the relationships between amylin and Aβ1-42 (β = +0.158, SE = 0.031, P<0.0001) or Aβ1-40 (β = +0.044, SE = 0.020, P = 0.03) in plasma still remained after adjusting for age, gender, ethnicity, BMI, diabetes, stroke, creatinine and the lipid profile (Tables 1 and 5). Careers. Fasting blood draws were conducted. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease. Future studies are necessary to examine the concentrations of amylin and its relationship to Aβ in specific diagnostic groups. This site needs JavaScript to work properly. While Aβ42 is a major component of AD pathology in the brain [29], Aβ40 is a component of cerebral amyloid angiopathy (CAA) [30]. Eur Arch Psychiatry Clin Neurosci. BBB dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Aβ from brain are all thought to contribute to AD pathogenesis [15]. No, Is the Subject Area "Diabetes mellitus" applicable to this article? the islet amyloid polypeptide (IAPP, or amylin) within islet -cells is a major pathological feature of the pancreas in patients with chronic T2D. 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 Amylin … here. In light of this effect, we hypothesized that endogenous amylin in blood would enhance the removal of Aβ from the brain, especially in elderly with amyloid pathology in the brain. All enrolled subjects gave written informed consent. 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. 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. ApoE4 was negatively associated with plasma Aβ1-42, but not with plasma Aβ1-40 in this model. Discover a faster, simpler path to publishing in a high-quality journal. Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p.) Click through the PLOS taxonomy to find articles in your field. 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. The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. broad scope, and wide readership – a perfect fit for your research every time. The positive association between amylin and Aβ1-40in blood disappeared in the presence of ApoE4 (Table 5). 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). 8600 Rockville Pike https://doi.org/10.1371/journal.pone.0088063.g001, https://doi.org/10.1371/journal.pone.0088063.t005. We divided subjects into ApoE4 non-carriers (n = 834) and ApoE4 carriers (n = 258) (Table 1). 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′). We found that concentrations of Aβ1-42 (P<0.0001) and Aβ1-40 (P<0.0001) increased with each quartile increase of amylin. A‐C,…, Amylin–amyloid beta (Aβ) cross‐seeding and…, Amylin–amyloid beta (Aβ) cross‐seeding and impaired cerebrospinal fluid (CSF)–brain Aβ exchange by high…, Decreased brain amylin amyloid‐core plaques…, Decreased brain amylin amyloid‐core plaques in APP/PS1 rats with genetically suppressed amylin secretion.…, Circulating aggregated amylin cross‐seeds with…, Circulating aggregated amylin cross‐seeds with brain amyloid beta (Aβ) in young APP/PS1 rats.…, National Library of Medicine The primary components of amyloid and fibril-forming molecules are called hIAPP (amylin and insulin). 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. A, Experimental protocol for intravenous amylin infusion in rats. Longitudinal studies are needed to confirm the causal relationship between high levels of plasma amylin and decreased Aβdeposition in the brain. 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]. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pone.0088063. No, Is the Subject Area "Alzheimer's disease" applicable to this article? Finally, the relationship between log10 of amylin and either log10 of plasma Aβ1-42 (β = +0.146, SE = 0.025, P<0.0001) or log10 of plasma Aβ1-40 (β = +0.034, SE = 0.016, P = 0.04) as an outcome persisted after adjusting for age, gender, ethnicity, ApoE4, BMI, diabetes, stroke, creatinine and lipid profile including cholesterol, LDL and HDL (Model III). 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. The average BMI was 31.6±8.6, and 37% had a history of diabetes (Table 1). Yes Amylin and insulin levels rise and fall in a synchronous manner . -, Martinez‐Valbuena I, Valenti‐Azcarate R, Amat‐Villegas I, et al. It influences blood sugar levels; when too much is secreted, risk for developing diabetes increases. 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, also known as islet amyloid polypeptide (IAPP), was discovered from pancreatic deposits of amyloid material from feline and human pancreas,. COVID-19 is an emerging, rapidly evolving situation. Another pancreatic peptide, insulin, is much less likely than amylin to be transported into the brain via the BBB [7], [8].
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