Platelet as a physiological model to investigate apoptotic mechanisms in Alzheimer beta-amyloid peptide production.
Although neuronal apoptosis in Alzheimer's disease is generally interpreted as the consequence of the toxicity of extracellular beta-amyloid (Abeta) peptide aggregates, some experimental results provide evidence that the Abeta overproduction can be the result of a primary neuronal degeneration. As platelets are considered a good model where to study proteolytic processing of the amyloid precursor protein (APP), we exposed platelets to the proapoptotic agent ionomycin and analyzed Abeta40 and Abeta42 levels in the intracellular and extracellular compartments. The activation of apoptotic pathways in platelets has been verified by mitochondrial membrane depolarization, exposure of phosphatidylserine, protease activation and morphological changes. A significative increase in intraplatelet Abeta40, but not Abeta42, was observed after 10 min treatment with ionomycin. Thus, the activation of apoptotic pathways in platelets determines an altered processing of APP leading to elevated levels of intracellular Abeta40. The specific intracellular production of Abeta40 represents a potential threat to the cells since very high local Abeta40 concentration increases the risk of its aggregation and toxicity. As a result, Abeta40 might be dangerous even before it becomes secreted rendering neurons highly vulnerable.
Casoli
Tiziana
T
Neurobiology of Aging Laboratory, INRCA Research Department, Via Birarelli 8, 60121 Ancona, Italy. t.casoli@inrca.it
Di Stefano
Giuseppina
G
Giorgetti
Belinda
B
Balietti
Marta
M
Recchioni
Rina
R
Moroni
Fausto
F
Marcheselli
Fiorella
F
Bernardini
Gianni
G
Fattoretti
Patrizia
P
Bertoni-Freddari
Carlo
C
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D017209:Apoptosis; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008954:Models, Biological; D010446:Peptide Fragments / Q000096:biosynthesis*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D015759:Ionomycin