Cholinesterase inhibitors influence APP metabolism in Alzheimer disease patients.
Platelets mirror pathogenic alterations in the central nervous system of Alzheimer disease (AD) patients: an alteration of the Amyloid Precursor Protein (APP) forms pattern and decreased alpha-secretase activity--the non-amyloidogenic APP processing enzyme--were demonstrated. Platelets were analysed at baseline and after 30 days of cholinesterase inhibitor (ChEI) treatment (T30). ADAM10 levels, alpha- and beta-secretase activity were assessed measuring ADAM10 immunoreactivity, sAPPalpha release and the membrane-attached C-terminal fragments produced by beta- and alpha-secretase cleavage, that is, CTF99 and CTF83, respectively. ChEIs treatment rescues impaired APP metabolism increasing significantly ADAM10 levels (T30 vs. T0, P < 0.05), alpha-secretase activity (T30 vs. T0, P < 0.05) and reducing beta-secretase cleavage (T30 vs. T0, P < 0.05). Restoration of the balance between the mutually exclusive alpha- and beta-secretase pathway in APP processing caused by short-term ChEIs treatment potentially represents a key event in AD therapy linking in vivo cholinergic effect to APP metabolism. The use of platelets may represent a useful tool to follow molecular aspects of pharmacological response in AD patients.
Zimmermann
Martina
M
Centre of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. Martina.Zimmerman@unimi.it
Borroni
Barbara
B
Cattabeni
Flaminio
F
Padovani
Alessandro
A
Di Luca
Monica
M
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors