title: Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.
abstract: Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD.
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Kaufman
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Haakon B
authors.initials: HB
authors.lastname: Nygaard
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and.
authors.forename: Pujan
authors.initials: P
authors.lastname: Patel
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Haas
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Gunther
authors.affiliation: the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06536 and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vortmeyer
authors.affiliation: From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520 stephen.strittmatter@yale.edu.
authors.forename: Stephen M
authors.identifier: http://orcid.org/0000-0001-8188-3092
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008875:Middle Aged; D008970:Molecular Weight; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018621:PrPC Proteins; D053764:Presenilin-1; D011328:Prions; D011994:Recombinant Proteins; C580804:presenilin 1, mouse
keywords: Alzheimer disease; amyloid-beta (AB); learn; ligand-binding protein; memory; oligomer; prion; transgenic mice