title: Chemical modifications of amyloid-β(1-42) have a significant impact on the repertoire of brain amyloid-β(1-42) binding proteins.
abstract: The amyloid-β peptide(1-42) (Aβ) is a key player in the development and progression of Alzheimer's disease (AD). Although much attention is paid to its role in formation of extracellular amyloid plaques and protein aggregates as well as to corresponding mechanisms of their toxicity, good evidence exists that intracellular Aβ can accumulate intraneuronally and interact with intracellular target proteins. However, intracellular Aβ binding proteins as well as conditions favoring their interactions with Aβ are poorly characterized. In this study we have investigated the effect of two known pathogenic Aβ modifications, isomerization of Asp7 and phosphorylation of Ser8, on the proteomic profiles of mouse brain Aβ binding proteins. Phosphorylation of Ser8 and especially isomerization of Asp7 significantly extended the repertoire of mouse brain Aβ binding proteins. However, there were 61 proteins, common for three types of the affinity ligands. They obviously represent potential targets for direct interaction with all Aβ species. Taking into consideration spontaneous mode of Asp7 isomerization and reports on initial accumulation of phosphorylated Aβ species inside neurons it is reasonable to suggest that these modifications of intracellular Aβ peptides causing the significant increase in the repertoire of Aβ binding proteins represent a primary pathogenic effect that precedes formation of extracellular pathogenic oligomerization/aggregation of Aβ peptides well described in the literature.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia; Institute of Biomedical Chemistry, 10 Pogodinskaya Street, Moscow 119121, Russia. Electronic address: professor57@yandex.ru.
authors.forename: Alexei E
authors.initials: AE
authors.lastname: Medvedev
authors.affiliation: Institute of Biomedical Chemistry, 10 Pogodinskaya Street, Moscow 119121, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Buneeva
authors.affiliation: Institute of Biomedical Chemistry, 10 Pogodinskaya Street, Moscow 119121, Russia.
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Kopylov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Mitkevich
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozin
authors.affiliation: Institute of Biomedical Chemistry, 10 Pogodinskaya Street, Moscow 119121, Russia.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Zgoda
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Makarov
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007536:Isomerism; D013058:Mass Spectrometry; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D012694:Serine / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D010446:Peptide Fragments; D020543:Proteome; C075222:amyloid beta-protein (1-42); D001224:Aspartic Acid; D012694:Serine
keywords: Amyloid-β; Amyloid-β binding proteins; IsoAsp7-Aβ; Mouse brain; Proteomic profiling; pSer8-Aβ