Discovering and targeting the basic mechanism of neurodegeneration: The role of peptides from the C-terminus of acetylcholinesterase

Acetylcholinesterase (AChE) is now well-established widely as a signalling molecule with non-hydrolytic functions including trophic activity in a diverse variety of situations in both neural and non-neural tissues. We have focussed on the observation that AChE, operating as a trophic agent independent of its enzymatic action, does indeed trigger calcium entry into neurons. It is possible that AChE has a dual non-classical action that ranges along a trophic-toxic axis, depending on amount, duration of availability and, most significantly, age. The neurodegenerative diseases could therefore be viewed as aberrant activation of developmental mechanisms with 'non-cholinergic' AChE as a, perhaps the, pivotal molecule. We have identified two peptides that could be cleaved from the C-terminus of T-AChE, one (T14), within the other (T30), and which have a strong sequence homology to the comparable region of beta-amyloid whilst the inert residue within the T30 sequence ('T15') acts as a control, and is without effect. We have subsequently been able to ascribe the trophic-toxic actions of the both T14 and T30 peptides to the modulation of calcium influx via an allosteric site on the alpha-7 nicotinic acetylcholine receptor (α7-nAChR). If the scenario described here is indeed the primary mechanism of neurodegeneration, then interception of the actions of the 'non-cholinergic' AChE-peptides T14 and T30 at the α7-nAChR, would be a promising novel therapy for arresting and stabilising cell loss in Alzheimer's disease, whereas detection of the peptides ideally in the blood, could provide a sensitive surrogate marker. If the marker was sensitive enough to be detected pre-symptomatically in a routine blood test, then the medication for arresting further cell loss could be initiated at that time, and the symptoms would never appear. This dual approach of identifying the marker and then intercepting its further action, could thus amount to an effective treatment for Alzheimer's and other neurodegenerative diseases.