Role of acetylcholinesterase inhibitors in pharmacological regulation of amyloid precursor protein processing

Abstract

The triggering events leading to the selective neurodegeneration observed in Alzheimer brains are not yet completely understood. They thus create a great challenge for the definition of a resolutive treatment for the causes and symptoms of Alzheimer's Disease (AD). Since the current therapeutic option for AD patients is the use of acetylcholinesterase inhibitors (AChEIs), several authors have examined whether these drugs can also affect the expression and metabolism of the amyloid precursor protein (AbetaPP). The rationale behind these studies was based on the fact that the literature suggests that cholinergic activities are also involved in the regulation of AbetaPP metabolism. Therefore, the characterization of these aspects of AD pharmacology may allow cholinergic drugs to be tested for their ability to intervene at different levels of the pathogenetic chain, other than providing a replacement therapy for lost neurotransmitters. This paper reviews the evidence that many of these drugs, although with different qualitative effects, are able to modulate the metabolism and expression of AbetaPP. This effect is often sustained by an indirect cholinergic mechanism and does not affect the mRNA expression of the precursor, although some other authors have demonstrated an effect on post-transcriptional regulation of AbetaPP expression. In addition to the effect on AbetaPP processing, we recently explored the possibility that these molecules affect a gene expression program beyond the classical pharmacological effects, for insights on possibly unexplored pathways of intervention in AD.