Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults

Zhu, Haihao; Qin, Tao; Ang, Ting Fang Alvin; Massaro, Joseph M.; Gan, Qini; Salim, Saraf; Zhu, Rui; Kolachalama, Vijaya B.; Zhang, Xiaoling; Devine, Sheral; Auerbach, Sanford H.; DeCarli, Charles; Au, Rhoda; Qiu, Wei Qiao

doi:10.1001/jamanetworkopen.2019.9826

Cited by 22 publications

(23 citation statements)

References 42 publications

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“…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. 27 If amylin lowers Aβ pathology, we then should expect that genetically suppressed amylin gene in APP/PS1 rats will exacerbate AD pathology and behavior deficits, whereas overexpressing amylin will slow disease progression. 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 amyloidforming human amylin in murine AD mice exacerbate cerebral amyloid burden through cumulative diabetogenic effects of the coexpressed human amylin and Aβ.…”

Section: Discussionmentioning

confidence: 99%

“…These results directly address the potential for modulation of circulating amylin as a means to alter AD pathology. 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 27 . If amylin lowers Aβ pathology, we then should expect that genetically suppressed amylin gene in APP/PS1 rats will exacerbate AD pathology and behavior deficits, whereas overexpressing amylin will slow disease progression.…”

Section: Discussionmentioning

confidence: 99%

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The association of circulating amylin with β‐amyloid in familial Alzheimer's disease

Verma

Sharma

et al. 2021

A&D Transl Res & Clin Interv

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Introduction:This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).Methods: 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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The association of circulating amylin with β‐amyloid in familial Alzheimer's disease

Verma

Sharma

et al. 2021

A&D Transl Res & Clin Interv

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“…However, amylin can aggregate when concentrations are high and become neurotoxic in cell cultures and is associated with brain amyloid burden and cognitive impairment in AD [38,39]. Recent studies have also indicated that the high plasma levels of IAPP is a pathological hallmark of insulin resistance [40] and correlates with AD diagnosis and brain structure [41]. In vitro studies revealed that curcumin significantly reduces h-IAPP fibril formation and aggregates formed in the presence of curcumin display alternative structure compared to the actual peptide [42].…”

Section: Discussionmentioning

confidence: 99%

Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3β and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer’s Disease

et al. 2020

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Dietary supplementation with curcumin has been previously reported to have beneficial effects in people with insulin resistance, type 2 diabetes (T2D) and Alzheimer's disease (AD). This study investigated the effects of dietary supplementation with curcumin on key peptides implicated in insulin resistance in individuals with high risk of developing T2D. Plasma samples from participants recruited for a randomised controlled trial with curcumin (180 mg/day) for 12 weeks were analysed for circulating glycogen synthase kinase-3 β (GSK-3β) and islet amyloid polypeptide (IAPP). Outcome measures were determined using ELISA kits. The homeostasis model for assessment of insulin resistance (HOMA-IR) was measured as parameters of glycaemic control. Curcumin supplementation significantly reduced circulating GSK-3β (−2.4 ± 0.4 ng/mL vs. −0.3 ± 0.6, p = 0.0068) and IAPP (−2.0 ± 0.7 ng/mL vs. 0.4 ± 0.6, p = 0.0163) levels compared with the placebo group. Curcumin supplementation significantly reduced insulin resistance (−0.3 ± 0.1 vs. 0.01 ± 0.05, p = 0.0142) compared with placebo group. Dietary supplementation with curcumin reduced circulating levels of IAPP and GSK-3β, thus suggesting a novel mechanism through which curcumin could potentially be used for alleviating insulin resistance related markers for reducing the risk of T2D and AD.

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“…Amylin amyloid deposition in the pancreas is a well-recognized hallmark feature of T2D. ,, Recently, amylin amyloid deposition was also found in the brains of T2D patients with dementia or Alzheimer’s disease, as well as in the brains of diabetic HIP animal models, raising the possibility that amylin amyloid may be a new amyloid in the brain. ,,,, The exact mechanism of such diabetes-induced neurodegeneration remains elusive. However, validating this new hypothesis will be highly significant, as it opens a new field by identifying a specific molecular link between diabetes and neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes

Velander

Wang

et al. 2021

ACS Pharmacol. Transl. Sci.

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Protein aggregation is associated with a large number of human protein-misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid (RA) as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200–300 nM). Structure–function relationship analysis of RA showed the additive effects of the two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin but rather lead to nontoxic, remodeled protein aggregates. RA has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of RA treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein-misfolding diseases.

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Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults

Abstract: This cohort study uses data from second-generation participants in the Framingham Heart Study to analyze the association of plasma amylin concentration with Alzheimer disease risk and brain structure.

Cited by 22 publications

References 42 publications

The association of circulating amylin with β‐amyloid in familial Alzheimer's disease

The association of circulating amylin with β‐amyloid in familial Alzheimer's disease

Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3β and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer’s Disease

Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes

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