title: Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation.
abstract: The Alzheimer's disease Abeta peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Abeta and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-beta (Abeta), the fibrillar prion peptides PrP106-126 and PrP178-193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. Specificity was shown by a lack of change to amyloid precursor-like protein 1, tau-1 and cellular prion protein (PrP(c)) levels. APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that PrP106-126 and the non-toxic but fibril-forming PrP178-193 increased APP levels in cultures derived from both wild-type and PrP(c)-deficient mice indicating that fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and irrespective of parental protein expression. Fibrillar PrP106-126 and Abeta peptides bound recombinant APP and APLP2 suggesting the accumulation of these proteins was mediated by direct binding to the fibrillated peptide. This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18-146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders.
authors.affiliation: Department of Pathology, The University of Melbourne, 3010, Victoria, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Fran
authors.initials: F
authors.lastname: Maher
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Brazier
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jobling
authors.forename: James
authors.initials: J
authors.lastname: Thyer
authors.forename: Leanne R
authors.initials: LR
authors.lastname: Stewart
authors.forename: Andrew
authors.initials: A
authors.lastname: Thompson
authors.forename: Riki
authors.initials: R
authors.lastname: Gibson
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Barrow
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000145:classification / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008854:Microscopy, Electron / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000494:pharmacology; D011328:Prions / Q000145:classification / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins
chemical_list: C489697:APLP1 protein, human; C084104:APLP2 protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; C492952:Aplp2 protein, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011328:Prions; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); C082632:prion protein (106-126)