title: Amyloid-β 1-24 C-terminal truncated fragment promotes amyloid-β 1-42 aggregate formation in the healthy brain.
abstract: Substantial data indicate that amyloid-β (Aβ), the major component of senile plaques, plays a central role in Alzheimer's Disease and indeed the assembly of naturally occurring amyloid peptides into cytotoxic aggregates is linked to the disease pathogenesis. Although Aβ42 is a highly aggregating form of Aβ, the co-occurrence of shorter Aβ peptides might affect the aggregation potential of the Aβ pool. In this study we aimed to assess whether the structural behavior of human Aβ42 peptide inside the brain is influenced by the concomitant presence of N-terminal fragments produced by the proteolytic activity of glial cells. We show that the occurrence of the human C-terminal truncated 1-24 Aβ fragment impairs Aβ42 clearance through blood brain barrier and promotes the formation of Aβ42 aggregates even in the healthy brain. By showing that Aβ1-24 has seeding properties for aggregate formation in intracranially injected wild type mice, our study provide the proof-of-concept that peptides produced upon Aβ42 cleavage by activated glial cells may cause phenotypic defects even in the absence of genetic mutations associated with Alzheimer's Disease, possibly contributing to the development of the sporadic form of the pathology.
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.|Hertie Institute and Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Otfried-Müller-Straße 27, 72076, Tübingen, Germany.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mazzitelli
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.|Humanitas University, via Manzoni 56, 20089, Rozzano, Italy.
authors.forename: Fabia
authors.initials: F
authors.lastname: Filipello
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.|Humanitas University, via Manzoni 56, 20089, Rozzano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rasile
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Lauranzano
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Starvaggi-Cucuzza
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.|IN-CNR, via Vanvitelli 32, 20129, Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Tamborini
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pozzi
authors.affiliation: Humanitas University, via Manzoni 56, 20089, Rozzano, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Barajon
authors.affiliation: IN-CNR, Corso Stati Uniti 4, 35126, Padova, Italy.
authors.forename: Toni
authors.initials: T
authors.lastname: Giorgino
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Natalello
authors.affiliation: IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy. m.matteoli@in.cnr.it.|IN-CNR, via Vanvitelli 32, 20129, Milano, Italy. m.matteoli@in.cnr.it.
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007859:Learning Disabilities / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D055503:Protein Multimerization; D012919:Social Behavior
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C000620629:amyloid beta-peptide (1-24); C075222:amyloid beta-protein (1-42); D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Alzheimer’s disease; Amyloid-β; Aβ24; Microglia; Proteolytic activity