Cognitive effects of cell-derived and synthetically derived Aβ oligomers

Miranda N. Reed, Jacki J. Hofmeister, Lisa Jungbauer, Alfred T. Welzel, Chunjiang Yu, Mathew A. Sherman, Sylvain Lesné, Mary Jo LaDu, Dominic M. Walsh, Karen H. Ashe, James P. Cleary

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Soluble forms of amyloid-β peptide (Aβ) are a molecular focus in Alzheimer's disease research. Soluble Aβ dimers (≈8. kDa), trimers (≈12. kDa), tetramers (≈16. kDa) and Aβ*56 (≈56. kDa) have shown biological activity. These Aβ molecules have been derived from diverse sources, including chemical synthesis, transfected cells, and mouse and human brain, leading to uncertainty about toxicity and potency. Herein, synthetic Aβ peptide-derived oligomers, cell- and brain-derived low-n oligomers, and Aβ*56, were injected intracerebroventricularly (icv) into rats assayed under the Alternating Lever Cyclic Ratio (ALCR) cognitive assay. Cognitive deficits were detected at 1.3 μM of synthetic Aβ oligomers and at low nanomolar concentrations of cell-secreted Aβ oligomers. Trimers, from transgenic mouse brain (Tg2576), did not cause cognitive impairment at any dose tested, whereas Aβ*56 induced concentration-dependent cognitive impairment at 0.9 and 1.3 μM. Thus, while multiple forms of Aβ have cognition impairing activity, there are significant differences in effective concentration and potency.

Original languageEnglish (US)
Pages (from-to)1784-1794
Number of pages11
JournalNeurobiology of Aging
Volume32
Issue number10
DOIs
StatePublished - Oct 2011

Bibliographical note

Funding Information:
Antibodies 2G3 and 21F12 were generously supplied by Drs. D. Schenk and P. Seubert, Elan Pharmaceuticals, Inc. Dr. Cleary was funded under an ETS Walton Award from Science Foundation Ireland at Trinity College Dublin, Dublin, Republic of Ireland.

Funding Information:
Support and disclosure: We gratefully acknowledge support from NIH RO1 AG19121 (MJL), Alzheimer's Association NIRG-06-26957 (CY, JPC), Science Foundation of Ireland (JPC), and NIH 1F32 AG030256-01 (LMJ), and Wellcome Trust Grant 067660 (DMW). ATW is a recipient of EU Early Training Fellowship.

Keywords

  • Alzheimer's disease
  • Amyloid-β peptide
  • Cognition
  • Oligomers

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