| First Author | Chiang ACA | Year | 2018 |
| Journal | Am J Pathol | Volume | 188 |
| Issue | 3 | Pages | 739-756 |
| PubMed ID | 29248459 | Mgi Jnum | J:257517 |
| Mgi Id | MGI:6118034 | Doi | 10.1016/j.ajpath.2017.11.011 |
| Citation | Chiang ACA, et al. (2018) Discrete Pools of Oligomeric Amyloid-beta Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis. Am J Pathol 188(3):739-756 |
| abstractText | Despite increasing appreciation that oligomeric amyloid-beta (Abeta) 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 Abeta oligomers during the evolution of cognitive deficits in an aggressive model of Abeta 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 Abeta 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 Abeta 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 Abeta oligomers, whereas immunoprecipitation-Western blotting using high-detergent extracts revealed a variety of SDS-stable low-n species. These findings show that different Abeta oligomers vary in solubility, consistent with distinct localization, and identify nonfibrillar Abeta oligomer-positive aggregates as tracking most closely with cognitive decline in this model. |
