title: In vivo seeding and cross-seeding of localized amyloidosis: a molecular link between type 2 diabetes and Alzheimer disease.
abstract: Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (Aβ) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism. Proximity ligation assay was used for colocalization studies of IAPP and Aβ in islet amyloid in type 2 diabetic patients and Aβ deposits in brains of patients with Alzheimer disease. Aβ reactivity was not detected in islet amyloid although islet β cells express AβPP and convertases necessary for Aβ production. By contrast, IAPP and proIAPP were detected in cerebral and vascular Aβ deposits, and presence of proximity ligation signal at both locations showed that the peptides were <40 nm apart. It is not clear whether IAPP present in brain originates from pancreas or is locally produced. Heterologous seeding between IAPP and Aβ shown here may represent a molecular link between type 2 diabetes and Alzheimer disease.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Oskarsson
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan F
authors.initials: JF
authors.lastname: Paulsson
authors.affiliation: Centre for Cancer Biomedicine, Oslo University Hospital, Oslo, Norway.
authors.forename: Sebastian W
authors.initials: SW
authors.lastname: Schultz
authors.affiliation: Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Westermark
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Electronic address: gunilla.westermark@mcb.uu.se.
authors.forename: Gunilla T
authors.initials: GT
authors.lastname: Westermark
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; C422904:pro-islet amyloid polypeptide