This study assessed the hypothesis that circulating human amylin (amyloid‐forming) cross‐seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).
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.
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.
These findings strengthened the hypothesis of circulating amylin‐AD interaction and suggest that modulation of blood amylin levels may alter Aβ‐related pathology/symptoms.
Digital Object Identifier (DOI)
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.
Ly, Han Gia; 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; Alzheimer’s disease Exome Sequencing Group; and Despa, Florin, "The Association of Circulating Amylin with β-Amyloid in Familial Alzheimer's Disease" (2021). Pharmacology and Nutritional Sciences Faculty Publications. 114.
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