Role of acetylcholinesterase inhibitors in the regulation of amyloid β precursor protein (AβPP) metabolism

The events that lead to neurodegeneration in Alzheimer's brains are largely unknown and this fact creates a great challenge for the definition of treatments that may be resolutive for Alzheimer's disease (AD). The current therapeutic option for AD patients is the use of acetylcholinesterase inhibitors (AChEIs), which gives a symptomatic relief to some of the clinical manifestations of the disease. In addition, several authors investigated whether these drugs can also affect one of the major pathogenetic pathway postulated for the disease, that is the expression and metabolism of the amyloid precursor protein (AβPP). The literature suggests that cholinergic activities may be significantly involved in the regulation of AβPP metabolism, thus the characterisation of these aspects of AD pharmacology may allow testing cholinergic drugs in their ability to intervene at different levels of the pathogenetic chain, other than to provide a replacement therapy for lost neurotransmitters. In this paper we review the evidence that these drugs, albeit with different quantitative and qualitative effects, can modulate the metabolism and expression of AβPP, through mechanism that involve either an indirect cholinergic mechanism or effects that do not involve the canonical pharmacological activity of AChE inhibitors. We also provide preliminary evidence that these molecules may affect a gene expression program beyond the classical pharmacological pattern suggesting an insight on possible unexplored pathways of intervention in AD.