The association of circulating amylin with β-amyloid in familial Alzheimer's disease
Ly, Han; Verma, Nirmal; Sharma, Savita; Kotiya, Deepak; Despa, Sanda; Abner, Erin L; Nelson, Peter T; Jicha, Gregory A; Wilcock, Donna M; Goldstein, Larry B; Guerreiro, Rita; Brás, José; Hanson, Angela J; Craft, Suzanne; Murray, Andrew J; Biessels, Geert Jan; Troakes, Claire; Zetterberg, Henrik; Hardy, John; Lashley, Tammaryn; Aesg; Despa, Florin
(2021) Alzheimer's and Dementia: Translational Research and Clinical Interventions, volume 7, issue 1, pp. 1 - 11
(Article)
Abstract
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
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control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. Results: Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ42 concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. 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. Discussion: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms.
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Keywords: amylin, amyloid, familial Alzheimer’s disease, islet amyloid polypeptide, sporadic Alzheimer’s disease, Clinical Neurology, Psychiatry and Mental health, Journal Article
ISSN: 2352-8737
Publisher: Wiley
Note: Funding Information: ● UK Dementia Research Institute, which receives its funding from DRI Ltd, UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK; Funding Information: Funding in part by: ● 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); ● Dolby Family Fund; ● 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. is supported by an American Heart Association fellowship (18PRE33990154); ● Alzheimer's Association VMF-15-363458; ● T.L. is supported by an Alzheimer's Research UK Senior Fellowship; ● R.G. and J.B. received fellowships from the Alzheimer's Society. ● Resources from the University of Kentucky COVD Pathology Core were used in this study. Funding Information: Funding in part by: Publisher Copyright: © 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.
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