Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation

Recent studies support the hypothesis that soluble oligomers of amyloid beta-peptide (Abeta) 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-...

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Bibliographic Details
Published in:The Journal of neuroscience 2005-03, Vol.25 (10), p.2455-2462
Main Authors: Walsh, Dominic M, Townsend, Matthew, Podlisny, Marcia B, Shankar, Ganesh M, Fadeeva, Julia V, El Agnaf, Omar, Hartley, Dean M, Selkoe, Dennis J
Format: Article
Language:English
Subjects:
Amyloid - metabolism
Amyloid beta-Peptides - antagonists & inhibitors
Amyloid beta-Peptides - chemical synthesis
Amyloid beta-Peptides - metabolism
Animals
CHO Cells
Cricetinae
Diamines - pharmacology
Female
Hippocampus - drug effects
Hippocampus - metabolism
Long-Term Potentiation - drug effects
Long-Term Potentiation - physiology
Male
Mice
Peptide Fragments - antagonists & inhibitors
Peptide Fragments - chemical synthesis
Peptide Fragments - metabolism
Pyridazines - pharmacology
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Summary:Recent studies support the hypothesis that soluble oligomers of amyloid beta-peptide (Abeta) 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 Abeta oligomers to search for inhibitors of the pathobiological effects of natural human Abeta oligomers. Here, we identify small molecules that inhibit formation of soluble Abeta oligomers and thus abrogate their block of long-term potentiation (LTP). Furthermore, we show that cell-derived Abeta 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 Abeta 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 Abeta oligomerization under biologically relevant conditions.
ISSN:1529-2401