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

Dominic M. Walsh, Matthew Townsend, Marcia B. Podlisny, Ganesh M. Shankar, Julia V. Fadeeva, Omar Ali El-Agnaf, Dean M. Hartley, Dennis J. Selkoe

Research output: Contribution to journalArticle

252 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2455-2462
Number of pages8
JournalJournal of Neuroscience
Volume25
Issue number10
DOIs
Publication statusPublished - 9 Mar 2005
Externally publishedYes

Fingerprint

Long-Term Potentiation
Amyloid
Alzheimer Disease
Amyloid beta-Protein Precursor
Gel Chromatography
Cell Culture Techniques
Cell Line
peptide A
Therapeutics

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Fibrillogenesis
  • LTP
  • Oligomers
  • Size exclusion chromatography

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Certain inhibitors of synthetic amyloid β-peptide (Aβ) fibrillogenesis block oligomerization of natural Aβ and thereby rescue long-term potentiation. / Walsh, Dominic M.; Townsend, Matthew; Podlisny, Marcia B.; Shankar, Ganesh M.; Fadeeva, Julia V.; Ali El-Agnaf, Omar; Hartley, Dean M.; Selkoe, Dennis J.

In: Journal of Neuroscience, Vol. 25, No. 10, 09.03.2005, p. 2455-2462.

Research output: Contribution to journalArticle

Walsh, Dominic M. ; Townsend, Matthew ; Podlisny, Marcia B. ; Shankar, Ganesh M. ; Fadeeva, Julia V. ; Ali El-Agnaf, Omar ; Hartley, Dean M. ; Selkoe, Dennis J. / Certain inhibitors of synthetic amyloid β-peptide (Aβ) fibrillogenesis block oligomerization of natural Aβ and thereby rescue long-term potentiation. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 10. pp. 2455-2462.
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