title: The molecular assembly of amyloid aβ controls its neurotoxicity and binding to cellular proteins.
abstract: Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1-40 and Aβ 1-42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Valentina
authors.initials: V
authors.lastname: Diana
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Massimo
authors.initials: M
authors.lastname: Messa
authors.forename: Monica
authors.initials: M
authors.lastname: Lupi
authors.forename: Valentina
authors.initials: V
authors.lastname: Bonetto
authors.forename: Mauro
authors.initials: M
authors.lastname: Pignataro
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.forename: Erika
authors.initials: E
authors.lastname: Sironi
authors.forename: Alun
authors.initials: A
authors.lastname: Williams
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D026481:Blotting, Far-Western; D002402:Cathepsin D / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D055503:Protein Multimerization; D014746:Vimentin / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; D014746:Vimentin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002402:Cathepsin D