Additive Toxicity of β-Amyloid by a Novel Bioactive Peptide In Vitro: Possible Implications for Alzheimer's Disease

Sara García-Ratés, M. Lewis, Rosemary Worrall, Susan Greenfield

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    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. Findings: 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. Interpretation: 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. © 2013 Garcia-Ratés et al.
    Original languageEnglish
    Pages (from-to)Article number e54864
    JournalPLoS One
    Volume8
    Issue number2
    DOIs
    Publication statusPublished - 2013

    Fingerprint

    amyloid
    Alzheimer disease
    Acetylcholinesterase
    acetylcholinesterase
    Amyloid
    Toxicity
    Alzheimer Disease
    peptides
    toxicity
    Peptides
    Poisons
    cells
    Bioactivity
    lissamine rhodamine B
    Hydrogen Peroxide
    hydrogen peroxide
    Assays
    Cells
    adrenal medulla
    Dithionitrobenzoic Acid

    Cite this

    García-Ratés, Sara ; Lewis, M. ; Worrall, Rosemary ; Greenfield, Susan. / Additive Toxicity of β-Amyloid by a Novel Bioactive Peptide In Vitro: Possible Implications for Alzheimer's Disease. In: PLoS One. 2013 ; Vol. 8, No. 2. pp. Article number e54864.
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    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. Findings: 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. Interpretation: 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. {\circledC} 2013 Garcia-Rat{\'e}s et al.",
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    Additive Toxicity of β-Amyloid by a Novel Bioactive Peptide In Vitro: Possible Implications for Alzheimer's Disease. / García-Ratés, Sara; Lewis, M.; Worrall, Rosemary; Greenfield, Susan.

    In: PLoS One, Vol. 8, No. 2, 2013, p. Article number e54864.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Additive Toxicity of β-Amyloid by a Novel Bioactive Peptide In Vitro: Possible Implications for Alzheimer's Disease

    AU - García-Ratés, Sara

    AU - Lewis, M.

    AU - Worrall, Rosemary

    AU - Greenfield, Susan

    PY - 2013

    Y1 - 2013

    N2 - 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. Findings: 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. Interpretation: 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. © 2013 Garcia-Ratés et al.

    AB - 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. Findings: 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. Interpretation: 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. © 2013 Garcia-Ratés et al.

    U2 - 10.1371/journal.pone.0054864

    DO - 10.1371/journal.pone.0054864

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