[show abstract][hide abstract] ABSTRACT: Until recently, the only established function of acetylcholinesterase (AChE) was the termination of cholinergic neurotransmission. Therefore, the use of AChE inhibitors to treat symptoms caused by cholinergic imbalances in Alzheimer disease (AD) represented a rational approach. However, it is now clear that AChE and the cholinergic system may have broader effects in AD. Of particular interest may be signal transduction pathways mediated through cholinergic receptors that promote nonamyloidogenic amyloid precursor protein processing and decrease tau phosphorylation, and the role of AChE in the aggregation of beta-amyloid (Abeta) peptide. In addition, the neuronal and nonneuronal cholinergic systems have important roles in the modulation of regional cerebral blood flow. These findings may modify the overly simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment and ignores the potential of cholinergic therapies as disease-modifying agents. Chronic increases in AChE activity may exacerbate neurodegenerative processes, make clinically relevant levels of AChE inhibition more difficult to achieve, and cause the therapeutic value of cholinesterase inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear to increase AChE activity over the longer term whereas, remarkably, irreversible or very slowly reversible ChE-Is do not seem to have this effect. If such differences between ChE-Is are shown to have clinical correlates, this may prompt reconsideration of the rationale and expectations of some agents in the long-term management of AD.
[show abstract][hide abstract] ABSTRACT: Since the discovery of the cholinergic deficit in Alzheimer disease (AD), acetylcholinesterase (AChE) has been widely investigated in tissues involved in the disease. These studies showed modifications in AChE activity and changes in its polymorphism in brain as well as in cerebro-spinal fluid (CSF) and blood. The co-localization of the enzyme in the senile plaque provided evidence of its anomalous features. It has been also shown that AChE forms a stable complex with senile plaque components through its peripheral anionic site. Moreover, the neurotoxicity of amyloid components is increased by the presence of AChE. The occurrence of an altered glycosylation of some AChE forms in AD is closely related to the presence of amyloid formations. Literature on expression, relationships and modifications in the molecular polymorphism of AChE, in brain, CSF and blood in AD is reviewed.
Mechanisms of Ageing and Development 12/2001; 122(16):1961-9. · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The cholinergic hypothesis of Alzheimer disease (AD) has provided the rationale for the current pharmacotherapy of this disease, in an attempt to downgrade the cognitive decline caused by cholinergic deficits. Nevertheless, the search for potent and long-acting acetylcholinesterase (AChE) inhibitors that exert minimal side effects to AD patients is still an ongoing effort. Amazonian communities use traditional remedies prepared with Ptychopetalum olacoides (PO, Olacaceae) roots for treating various central nervous system conditions, including those associated with aging. The fact that PO ethanol extract (POEE) has been found to facilitate memory retrieval in the step down procedure in young and aged mice prompt us to evaluate its effects on AChE activity in memory relevant brain areas. POEE significantly inhibited AChE activity in vitro in a dose- and time-dependent manner in rat frontal cortex, hippocampus and striatum; a significant inhibition was also found in these same brain areas of aged (14 months) mice after acute administration of POEE (100 mg/kg ip). We propose that such AChE inhibitory activity is a neurochemical correlate of a number of therapeutic properties traditionally claimed for P. olacoides, particularly those associated with cognition.
Pharmacology Biochemistry and Behavior 07/2003; 75(3):645-50. · 2.61 Impact Factor
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