Role of acetylcholinesterase inhibitors in the regulation of amyloid beta precursor protein (AbetaPP) 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 (AbetaPP). The literature suggests that cholinergic activities may be significantly involved in the regulation of AbetaPP 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 AbetaPP, 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.
Racchi
Marco
M
Centre of Excellence in Applied Biology (CEBA), Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, Pavia 27100, Italy. racchi@unipv.it
Mazzucchelli
Michela
M
Lenzken
S Carolina
SC
Porrello
Emanuela
E
Lanni
Cristina
C
Govoni
Stefano
S
D000110:Acetylcholinesterase / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase