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The Journal of Neuroscience, March 9, 2005, 25(10):2455-2462; doi:10.1523/JNEUROSCI.4391-04.2005

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Neurobiology of Disease
Certain Inhibitors of Synthetic Amyloid -Peptide (A) Fibrillogenesis Block Oligomerization of Natural A and Thereby Rescue Long-Term Potentiation

Dominic M. Walsh,^1,2 * Matthew Townsend,^1 * Marcia B. Podlisny,¹ Ganesh M. Shankar,¹ Julia V. Fadeeva,¹ Omar El Agnaf,³ Dean M. Hartley,¹ and Dennis J. Selkoe¹

¹Department of Neurology, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, ²Laboratory for Neurodegenerative Research, The Conway Institute for Biomedical and Biomolecular Research, University College Dublin, Dublin 4, United Kingdom, and ³Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

Recent studies support the hypothesis that soluble oligomers of amyloid -peptide (A) rather than mature amyloid fibrils are the earliest effectors of synaptic compromise in Alzheimer's disease. We took advantage of an amyloid precursor protein-overexpressing cell line that secretes SDS-stable A oligomers to search for inhibitors of the pathobiological effects of natural human A oligomers. Here, we identify small molecules that inhibit formation of soluble A oligomers and thus abrogate their block of long-term potentiation (LTP). Furthermore, we show that cell-derived A oligomers can be separated from monomers by size exclusion chromatography under nondenaturing conditions and that the isolated, soluble oligomers, but not monomers, block LTP. The identification of small molecules that inhibit early A oligomer formation and rescue LTP inhibition offers a rational approach for therapeutic intervention in Alzheimer's disease and highlights the utility of our cell-culture paradigm as a useful secondary screen for compounds designed to inhibit early steps in A oligomerization under biologically relevant conditions.

Key words: Alzheimer's disease; amyloid -peptide; oligomers; LTP; size exclusion chromatography; fibrillogenesis

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Received Oct 21, 2004; revised January 18, 2005; accepted January 18, 2005.

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