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Am J Pathol. 2018 Mar;188(3):739-756. doi: 10.1016/j.ajpath.2017.11.011. Epub 2017 Dec 15.

Discrete Pools of Oligomeric Amyloid-β Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis.

Author information

1
Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas.
2
Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas; Department of Cognitive Science, Rice University, Houston, Texas.
3
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota.
5
Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas; Department of Neurology and Neurosurgery, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas. Electronic address: jankowsk@bcm.edu.

Abstract

Despite increasing appreciation that oligomeric amyloid-β (Aβ) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Herein, using a broad approach, we quantified Aβ oligomers during the evolution of cognitive deficits in an aggressive model of Aβ amyloidosis. Amyloid precursor protein/tetracycline transactivator mice underwent behavioral testing at 3, 6, 9, and 12 months of age to evaluate spatial learning and memory, followed by histologic assessment of amyloid burden and biochemical characterization of oligomeric Aβ species. Transgenic mice displayed progressive impairments in acquisition and immediate recall of the trained platform location. Biochemical analysis of cortical extracts from behaviorally tested mice revealed distinct age-dependent patterns of accumulation in multiple oligomeric species. Dot blot analysis demonstrated that nonfibrillar Aβ oligomers were highly soluble and extracted into a fraction enriched for extracellular proteins, whereas prefibrillar species required high-detergent conditions to retrieve, consistent with membrane localization. Low-detergent extracts tested by 82E1 enzyme-linked immunosorbent assay confirmed the presence of bona fide Aβ oligomers, whereas immunoprecipitation-Western blotting using high-detergent extracts revealed a variety of SDS-stable low-n species. These findings show that different Aβ oligomers vary in solubility, consistent with distinct localization, and identify nonfibrillar Aβ oligomer-positive aggregates as tracking most closely with cognitive decline in this model.

PMID:
29248459
PMCID:
PMC5840490
DOI:
10.1016/j.ajpath.2017.11.011
[Indexed for MEDLINE]
Free PMC Article

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