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J Biol Chem. 2015 Jul 10;290(28):17415-38. doi: 10.1074/jbc.M115.643577. Epub 2015 May 27.

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.

Author information

1
From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and.
2
From the Program in Cellular Neuroscience, Neurodegeneration, and Repair and the Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520.
3
the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06536 and.
4
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.

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.

KEYWORDS:

Alzheimer disease; amyloid-beta (AB); learn; ligand-binding protein; memory; oligomer; prion; transgenic mice

PMID:
26018073
PMCID:
PMC4498078
DOI:
10.1074/jbc.M115.643577
[Indexed for MEDLINE]
Free PMC Article

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