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-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.
Walsh
Dominic M
DM
Department of Neurology, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115-5716, USA.
Townsend
Matthew
M
Podlisny
Marcia B
MB
Shankar
Ganesh M
GM
Fadeeva
Julia V
JV
El Agnaf
Omar
O
Hartley
Dean M
DM
Selkoe
Dennis J
DJ
D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003959:Diamines / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D003959:Diamines; C472970:N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine; D010446:Peptide Fragments; D011724:Pyridazines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)