title: Additive toxicity of β-amyloid by a novel bioactive peptide in vitro: possible implications for Alzheimer's disease.
abstract: BACKGROUND
  β-amyloid is regarded as a significant factor in Alzheimer's disease: but inefficient therapies based on this rationale suggests that additional signalling molecules or intermediary mechanisms must be involved in the actual initiation of the characteristic degeneration of neurons. One clue could be that acetylcholinesterase, also present in amyloid plaques, is aberrant in peripheral tissues such as blood and adrenal medulla that can be implicated in Alzheimer's disease. The aim of this study was to assess the bioactivity of a fragment of acetylcholinesterase responsible for its non-enzymatic functions, a thirty amino acid peptide ("T30") which has homologies with β-amyloid.
  
  
  METHODS
  Cell viability was measured by sulforhodamine B assay and also lactate dehydrogenase assay: meanwhile, changes in the status of living cells was monitored by measuring release of acetylcholinesterase in cell perfusates using the Ellman reagent.
  
  
  RESULTS
  T30 peptide and β-amyloid each have toxic effects on PC12 cells, comparable to hydrogen peroxide(.) However only the two peptides selectively then evoke a subsequent, enhanced release in acetylcholinesterase that could only be derived from the extant cells. Moreover, unlike hydrogen peroxide, the T30 peptide selectively shifted a sub-threshold dose of β-amyloid to a toxic effect, which also resulted in a comparable enhanced release of acetylcholinesterase.
  
  
  CONCLUSIONS
  This is the first study comparing directly the bioactivity of β-amyloid with a peptide derived from acetylcholinesterase: the similarity in action suggests that the sequence homology between the two compounds might have a functional and/or pathological relevance. The subsequent enhanced release of acetylcholinesterase from the extant cells could reflect a primary 'compensatory' response of cells prone to degeneration, paradoxically providing further availability of the toxic C-terminal peptide to modulate the potency of β-amyloid. Such a cycle of events may provide new insights into the mechanism of continuing selective cell loss in Alzheimer's disease and related degenerative disorders.
authors: Department of Pharmacology, University of Oxford, Oxford, United Kingdom. sara.garciarates@pharm.ox.ac.uk
authors: Sara
authors: S
authors: Garcia-Ratés
authors: Matthew
authors: M
authors: Lewis
authors: Rosemary
authors: R
authors: Worrall
authors: Susan
authors: S
authors: Greenfield
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity*; D058225:Plaque, Amyloid / Q000737:chemistry; D051381:Rats; D012235:Rhodamines; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012235:Rhodamines; C022027:lissamine rhodamine B; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D000110:Acetylcholinesterase
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