The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention

D. M. Walsh, I. Klyubin, G. M. Shankar, M. Townsend, J. V. Fadeeva, V. Betts, M. B. Podlisny, James P Cleary, Karen H Ashe, M. J. Rowan, D. J. Selkoe

Research output: Contribution to journalArticle

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Abstract

Burgeoning evidence suggests that soluble oligomers of Aβ (amyloid β-protein) are the earliest effectors of synaptic compromise in Alzheimer's disease. Whereas most other investigators have employed synthetic Aβ peptides, we have taken advantage of a β-amyloid precursor protein-overexpressing cell line (referred to as 7PA2) that secretes sub-nanomolar levels of low-n oligomers of Aβ. These are composed of heterogeneous Aβ peptides that migrate on SDS/PAGE as dimers, trimers and tetramers. When injected into the lateral ventricle of rats in vivo, these soluble oligomers inhibit hippocampal long-term potentiation and alter the memory of a complex learned behaviour. Biochemical manipulation of 7PA2 medium including immunodepletion with Aβ-specific antibodies and fractionation by size-exclusion chromatography allowed us to unambiguously attribute these effects to low-n oligomers. Using this paradigm we have tested compounds directed at three prominent amyloid-based therapeutic targets: inhibition of the secretases responsible for Aβ production, inhibition of Aβ aggregation and immunization against Aβ. In each case, compounds capable of reducing oligomer production or antibodies that avidly bind Aβ oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers.

Original languageEnglish (US)
Pages (from-to)1087-1090
Number of pages4
JournalBiochemical Society transactions
Volume33
Issue number5
DOIs
StatePublished - Nov 1 2005

Fingerprint

Oligomers
Alzheimer Disease
Serum Amyloid A Protein
Amyloid Precursor Protein Secretases
Peptides
Long-Term Potentiation
Amyloid beta-Protein Precursor
Lateral Ventricles
Amyloid
Antibody Formation
Gel Chromatography
Polyacrylamide Gel Electrophoresis
Immunization
Research Personnel
Cell Line
Antibodies
Therapeutics
Size exclusion chromatography
Fractionation
Inhibition (Psychology)

Keywords

  • Alternating lever cyclic ratio
  • Alzheimer's disease
  • Amyloid β-protein
  • Long-term potentiation
  • Oligomer
  • Size-exclusion chromatography

Cite this

Walsh, D. M., Klyubin, I., Shankar, G. M., Townsend, M., Fadeeva, J. V., Betts, V., ... Selkoe, D. J. (2005). The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention. Biochemical Society transactions, 33(5), 1087-1090. https://doi.org/10.1042/BST20051087

The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention. / Walsh, D. M.; Klyubin, I.; Shankar, G. M.; Townsend, M.; Fadeeva, J. V.; Betts, V.; Podlisny, M. B.; Cleary, James P; Ashe, Karen H; Rowan, M. J.; Selkoe, D. J.

In: Biochemical Society transactions, Vol. 33, No. 5, 01.11.2005, p. 1087-1090.

Research output: Contribution to journalArticle

Walsh, DM, Klyubin, I, Shankar, GM, Townsend, M, Fadeeva, JV, Betts, V, Podlisny, MB, Cleary, JP, Ashe, KH, Rowan, MJ & Selkoe, DJ 2005, 'The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention', Biochemical Society transactions, vol. 33, no. 5, pp. 1087-1090. https://doi.org/10.1042/BST20051087
Walsh, D. M. ; Klyubin, I. ; Shankar, G. M. ; Townsend, M. ; Fadeeva, J. V. ; Betts, V. ; Podlisny, M. B. ; Cleary, James P ; Ashe, Karen H ; Rowan, M. J. ; Selkoe, D. J. / The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention. In: Biochemical Society transactions. 2005 ; Vol. 33, No. 5. pp. 1087-1090.
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