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Low blood amylin delays Alzheimer’s pathology by modulating brain hypoxia and amyloid composition: A study in humans and rats
Author(s) -
Despa Florin
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.045107
Subject(s) - amylin , amyloid (mycology) , endocrinology , medicine , cerebrospinal fluid , psen1 , genetically modified mouse , alzheimer's disease , amyloid precursor protein , transgene , pathology , biology , diabetes mellitus , disease , gene , islet , biochemistry
Background Decreased amyloid‐β (Aβ) 42 level in the cerebrospinal fluid (CSF) reflects Aβ 42 accumulation in cerebral plaques and is a biomarker for Alzheimer’s disease (AD). Histopathological analyses of brain tissues from individuals with sporadic AD showed that Aβ forms mixed deposits with the pancreatic amylin, a satiety hormone. Here we show that high blood amylin modifies CSF‐brain Aβ balance and brain amyloid composition in both sporadic AD and in PSEN1 and APP mutation carriers (familial AD), and that pancreatic hypersecretion of amylin in AD and non‐AD model rats accelerates behavioral deficits, whereas suppression of amylin expression is protective. Method We investigated the relationship between amylin and Aβ 42 levels in CSF from humans with early vs. late stage sAD, and between amylin and the brain in PSEN1 and APP mutation carriers, as these mutations have known biochemical effects on AD pathology; experiments in rats and cell models were used to define the mechanism. Specifically, we created transgenic AD and non‐AD rat models in which the consequences of elevated blood levels of human amylin can be directly addressed in terms of CSF‐brain Aβ balance, blood‐brain barrier (BBB) permeability to amylin, development of AD pathology and behavior deficits. To further test the mechanism, we intravenously injected human amylin in AD rats that express rat amylin. AD rats with the amylin gene deleted were generated to test effects of suppression of amylin secretion on AD pathology‐associated neurological score. Result We found that high circulating levels of amylin disrupts CSF‐brain Aβ balance via amylin‐Aβ cross‐seeding. Pancreatic hypersecretion of amylin in rats induced brain hypoxia signaling by amylin deposition in brain capillaries that altered neuronal metabolic pathways leading to increased Aβ synthesis and deposition in the brain. Similar mechanisms were triggered by intravenous injection of human amylin in rats. Amylin hypersecretion in APP/PS1 rats lowers neurologic score, whereas amylin gene deletion delays the development of AD pathology and behavioral changes. Conclusion Our results provide evidence of a role of amylin in modulating brain hypoxia and amyloid composition in both familial and sporadic forms of AD, and suggest that blood amylin may be a therapeutic target for early AD stage.