Abstract
Backgroundβ-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.MethodsCell 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.FindingsT30 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.InterpretationThis 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.
Highlights
It is well accepted that b-Amyloid (Ab) plays an important role in the pathogenesis of Alzheimer’s disease (AD), its precise contribution to the basic mechanism of neurodegeneration remains questionable
Acetylcholinesterase (AChE) is contained in all the vulnerable central nervous system (CNS) neurons prone to neurodegeneration, irrespective of the transmitter they use: we have proposed that the neurotoxic actions of the C-terminal peptides derived from AChE as a signal molecule could be the common mechanism for Parkinson’s disease, Motor neurone disease and AD [2]
Given that cell lines derived from the chromaffin cells of the adrenal medulla are a powerful in vitro tool, the aim of this study was to see whether the effects of bioactive agents, ie C-terminal peptides and Ab, can be reflected in changes in cell viability and subsequent release of AChE
Summary
It is well accepted that b-Amyloid (Ab) plays an important role in the pathogenesis of Alzheimer’s disease (AD), its precise contribution to the basic mechanism of neurodegeneration remains questionable. Within the C-terminal amino acid sequence of the AChE the 14 mer T14 is the active region that has a close homology to the sequence of Ab (Fig. 1). The residual 15 amino acid sequence, T15, was used as a control for non-specific peptide effect [2]. These peptides (T14 and T30) mimic the ‘non-cholinergic’ actions reported previously, have effects that can be both acute and chronic, and range along a trophic-toxic axis of excitotoxicity depending on duration and dose of administration, in a wide range of preparations [5]
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