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

ABSTRACT

INTRODUCTION: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aß) 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-Aß cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aß42 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 Aß exchange and amylin-Aß cross-seeding. DISCUSSION: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aß-related pathology/symptoms.