Inhibition of Cholinesterase (ChE) is the current standard for symptomatic therapy of Alzheimer's disease (AD) aimed at supporting the function and/or maintaining the integrity of the damaged cholinergic system. The various ChE inhibitors (ChE-I) currently in clinical use have differing properties in terms of enzyme selectivity and mechanism of inhibition. There is now growing evidence that two types of ChEs play a role in the regulation of cholinergic transmission in AD brain: (i) acetylcholinesterase (AChE) which specifically catalyses the hydrolysis of acetylcholine (ACh) and (ii) butyrylcholinesterase (BChE) which degrades in addition to ACh a wider range of choline esters. The two ChEs, evolutionarily conserved enzymes sharing an extensive sequence homology, were discerned based on their distinct substrate specificity and inhibitor sensitivity. The presence of ChEs in non-cholinergically innervated tissues provides the most compelling evidence for the view that AChE and BChE may also have functions unrelated to the termination of cholinergic neurotransmission. There is now a considerable body of evidence suggesting that ChEs are involved in embryonic neural development, including cell proliferation, differentiation and cell adhesion. ChEs may also have a causative/permissive role in various pathological conditions as exemplified by the presence of both abnormal activities of ChEs and altered properties in AD. The ability of both AChE and BChE to act as peptidases was established 20 years ago and it has been proposed that this °®second' property may be involved in the transformation of the amyloid deposit from a diffuse to a compact form or from a non-neuritic to a neuritic stage. Inestrosa et al. have demonstrated that AChE interacts with amyloid ©¬-peptide and promotes amyloid fibril formation independent from its catalytic machinery. ChE inhibitors were found to influence the secretion and processing of amyloid precursor protein (APP) in cholinergic lesioned animals. Enzyme activities other than the ©¬- or a-secretases are responsible for the formation and accumulation of APP-derived peptides in AD brains e.g. pyrrolidone carboxyl peptidases and interestingly enough (some) ChE inhibitors also interact with this enzyme. In conclusion, ChE inhibitors may influence, depending on their divergent properties, the APP processing and, as a direct consequence, also A©¬ formation. Obviously, such ameliorating effects in AD are distinct from action at the level of ChE inhibition. This suggests that ChE inhibitors, in addition to their well-known symptomatic amelioration, might also have a prominent effect on disease stabilization and/or progression.
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