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

Angie C.A. Chiang, Stephanie W. Fowler, Rohit Reddy, Olga Pletnikova, Juan C. Troncoso, Mathew A. Sherman, Sylvain E. Lesne, Joanna L. Jankowsky

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)739-756
Number of pages18
JournalAmerican Journal of Pathology
Volume188
Issue number3
DOIs
StatePublished - Mar 1 2018

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Amyloidosis
Amyloid
Detergents
Trans-Activators
Amyloid beta-Protein Precursor
Tetracycline
Short-Term Memory
Solubility
Transgenic Mice
Alzheimer Disease
Enzyme-Linked Immunosorbent Assay
Membranes
Spatial Learning
Proteins
Cognitive Dysfunction

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Discrete Pools of Oligomeric Amyloid-β Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis. / Chiang, Angie C.A.; Fowler, Stephanie W.; Reddy, Rohit; Pletnikova, Olga; Troncoso, Juan C.; Sherman, Mathew A.; Lesne, Sylvain E.; Jankowsky, Joanna L.

In: American Journal of Pathology, Vol. 188, No. 3, 01.03.2018, p. 739-756.

Research output: Contribution to journalArticle

Chiang, Angie C.A. ; Fowler, Stephanie W. ; Reddy, Rohit ; Pletnikova, Olga ; Troncoso, Juan C. ; Sherman, Mathew A. ; Lesne, Sylvain E. ; Jankowsky, Joanna L. / Discrete Pools of Oligomeric Amyloid-β Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis. In: American Journal of Pathology. 2018 ; Vol. 188, No. 3. pp. 739-756.
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