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

Han Ly; Nirmal Verma; Savita Sharma; Deepak Kotiya; Sanda Despa; Erin L. Abner; Peter T. Nelson; Gregory A. Jicha; Donna M. Wilcock; Larry B. Goldstein; Rita Guerreiro; José Brás; Angela J. Hanson; Suzanne Craft; Andrew J. Murray; Geert Jan Biessels; Claire Troakes; Henrik Zetterberg; John Hardy; Tammaryn Lashley; Aesg; Florin Despa

doi:10.1002/trc2.12130

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

Han Ly, Nirmal Verma, Savita Sharma, Deepak Kotiya, Sanda Despa, Erin L. Abner, Peter T. Nelson, Gregory A. Jicha, Donna M. Wilcock, Larry B. Goldstein, Rita Guerreiro, José Brás, Angela J. Hanson, Suzanne Craft, Andrew J. Murray, Geert Jan Biessels, Claire Troakes, Henrik Zetterberg, John Hardy, Tammaryn LashleyAesg, Florin Despa

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 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.

Original language	English
Article number	e12130
Journal	Alzheimer's and Dementia: Translational Research and Clinical Interventions
Volume	7
Issue number	1
DOIs	https://doi.org/10.1002/trc2.12130
State	Published - 2021

Bibliographical 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.

ASJC Scopus subject areas

Clinical Neurology
Psychiatry and Mental health

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Ly, H., Verma, N., Sharma, S., Kotiya, D., Despa, S., Abner, E. L., Nelson, P. T., Jicha, G. A., Wilcock, D. M., Goldstein, L. B., Guerreiro, R., Brás, J., Hanson, A. J., Craft, S., Murray, A. J., Biessels, G. J., Troakes, C., Zetterberg, H., Hardy, J., ... Despa, F. (2021). The association of circulating amylin with β-amyloid in familial Alzheimer's disease. Alzheimer's and Dementia: Translational Research and Clinical Interventions, 7(1), [e12130]. https://doi.org/10.1002/trc2.12130

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title = "The association of circulating amylin with β-amyloid in familial Alzheimer's disease",

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 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.",

author = "Han Ly and Nirmal Verma and Savita Sharma and Deepak Kotiya and Sanda Despa and Abner, {Erin L.} and Nelson, {Peter T.} and Jicha, {Gregory A.} and Wilcock, {Donna M.} and Goldstein, {Larry B.} and Rita Guerreiro and Jos{\'e} Br{\'a}s and Hanson, {Angela J.} and Suzanne Craft and Murray, {Andrew J.} and Biessels, {Geert Jan} and Claire Troakes and Henrik Zetterberg and John Hardy and Tammaryn Lashley and Aesg and Florin Despa",

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: {\textcopyright} 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.",

year = "2021",

doi = "10.1002/trc2.12130",

language = "English",

volume = "7",

number = "1",

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Ly, H, Verma, N, Sharma, S, Kotiya, D, Despa, S , Abner, EL , Nelson, PT , Jicha, GA , Wilcock, DM , Goldstein, LB, Guerreiro, R, Brás, J, Hanson, AJ, Craft, S, Murray, AJ, Biessels, GJ, Troakes, C, Zetterberg, H, Hardy, J, Lashley, T, Aesg, & Despa, F 2021, 'The association of circulating amylin with β-amyloid in familial Alzheimer's disease', Alzheimer's and Dementia: Translational Research and Clinical Interventions, vol. 7, no. 1, e12130. https://doi.org/10.1002/trc2.12130

TY - JOUR

T1 - The association of circulating amylin with β-amyloid in familial Alzheimer's disease

AU - Ly, Han

AU - Verma, Nirmal

AU - Sharma, Savita

AU - Kotiya, Deepak

AU - Despa, Sanda

AU - Abner, Erin L.

AU - Nelson, Peter T.

AU - Jicha, Gregory A.

AU - Wilcock, Donna M.

AU - Goldstein, Larry B.

AU - Guerreiro, Rita

AU - Brás, José

AU - Hanson, Angela J.

AU - Craft, Suzanne

AU - Murray, Andrew J.

AU - Biessels, Geert Jan

AU - Troakes, Claire

AU - Zetterberg, Henrik

AU - Hardy, John

AU - Lashley, Tammaryn

AU - Aesg,

AU - Despa, Florin

N1 - 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.

PY - 2021

Y1 - 2021

N2 - 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. 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.

AB - 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. 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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DO - 10.1002/trc2.12130

M3 - Article

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VL - 7

IS - 1

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ER -

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

Abstract

Bibliographical note

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UN SDGs

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