FROM A FAMILIAR ENZYME TO A NOVEL TOXIN
For over 40 years it has been accepted that acetylcholinesterase (AChE) is present in a widespread range of neurons and non-neuronal cells without its normal substrate acetylcholine (ACh) and the synthesising enzyme choline acetyltransferase (ChAT) Could it have an additional, non-enzymatic function? This was our starting point.Although not a requirement for its familiar role in cholinergic transmission, AChE is released into CSF, detectable locally from brain areas linked to neurodegeneration such as the substantia nigra, where its secretion can be visualised in real-time and monitored on-line in the freely moving animal.
As a signalling molecule independent of cholinergic transmission, ie where its primary site can be irreversibly blocked with Soman, AChE has electrophysiological, biochemical/pharmacological, and behavioural actions which in all the studies cited above cannot be replicated by another enzyme (butyrycholinesterase) which will nonetheless also hydrolyse ACh.
This novel, non-enzymatic function of AChE is to promote cell growth: it has a non-cholinergic trophic action in organotypic cell cultures of rat midbrain, via activation of calcium influx.
However in higher doses, or for a protracted period of administration, the trophic action of AChE can turn toxic.
Since (a) AChE is present in all the cell populations primarily vulnerable in neurodegeneration, irrespective of the diverse transmitter systems and (b) calcium influx can switch from trophic to toxic effects dependent on age, then (c) neurodegeneration could be a region-selective, aberrant form of development, with ‘non-cholinergic AChE as the pivotal signalling molecule.
The crucial part of the AChE molecule has been identified as a 14mer peptide, ‘T14’ at the C-terminus with homology to amyloid-beta which as an independent agent enhances calcium currents, which in turn can have a trophic-toxic, ‘excitotoxic’ action.
The action of T14 is modulatory, ie enhancing calcium influx via an allosteric site on the alpha-7 receptor which leads to the secondary generation of amyloid and hyperphosphorylation of tau.
Sustained application of the T14 leads to further upregulation of the alpha-7 receptor. Hence the peptide is enhancing availability of its own target, and providing a feed-forward mechanism to continue the degenerative process.
The significance of T14 in neurodegeneration has now been proven directly as it is elevated in the brains and CSF of Alzheimer patients to levels corresponding to those seen in development.
The action of T14 in triggering an inappropriate recapitulation of development, via the alpha 7 receptor, also occurs in metastatic cancer cells, suggesting a general and basic underlying biological mechanism for cell signalling throughout the body that has as yet been undiscovered.