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- Title
Certain Inhibitors of Synthetic Amyloid β-Peptide (Aβ) Fibrillogenesis Block Oligomerization of Natural Aβ and Thereby Rescue Long-Term Potentiation.
- Authors
Walsh, Dominic M.; Townsend, Matthew; Podlisny, Marcia B.; Shankar, Ganesh M.; Fadeeva, Julia V.; El Agnaf, Omar; Hartley, Dean M.; Selkoe, Dennis J.
- Abstract
Recent studies support the hypothesis that soluble oligomers of amyloid β-peptide (Aβ) 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 Aβ oligomers to search for inhibitors of the pathobiological effects of natural human Aβ oligomers. Here, we identify small molecules that inhibit formation of soluble Aβ oligomers and thus abrogate their block of long-term potentiation (LTP). Furthermore, we show that cell derived Aβ 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 Aβ 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 Aβ oligomerization under biologically relevant conditions.
- Subjects
ALZHEIMER'S disease; AMYLOID beta-protein; OLIGOMERS; CELL lines; CHROMATOGRAPHIC analysis
- Publication
Journal of Neuroscience, 2005, Vol 25, Issue 10, p2455
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4391-04.2005