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

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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 languageEnglish
Article numbere12130
Pages (from-to)1-11
Number of pages11
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Volume7
Issue number1
DOIs
Publication statusPublished - 2021

Keywords

  • amylin
  • amyloid
  • familial Alzheimer’s disease
  • islet amyloid polypeptide
  • sporadic Alzheimer’s disease

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