Neuronal apoptosis is accompanied by amyloid beta-protein accumulation in the endoplasmic reticulum.
A series of evidences suggests that enhanced susceptibility to programmed cell death (PCD) is a major pathogenetic factor in Alzheimer's disease (AD). We investigated this issue, analyzing amyloid beta-protein (A beta) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280-290% secreted A beta occurred, in spite of a 20% metabolism and an unchanged A betaPP expression. The increased intracellular A beta reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus of beta PP, but only partially rescued A beta overproduction caused by staurosporine treatment. Our findings suggest that PCD fosters the physiological pathways of A beta production characteristic of neuronal cells, and they confirm the theory that unbalance of PCD is a central event in AD pathogenesis. Moreover, our data indicate that still unidentified cellular mechanisms, other than caspases activation, are responsible of the specific alteration of A betaPP processing during PCD.
Borghi
Roberta
R
Institute of Human Anatomy, Department of Experimental Medicine, University of Genova, Italy.
Pellegrini
Luca
L
Lacaná
Emanuela
E
Diaspro
Alberto
A
Pronzato
Maria Adelaide
MA
Vitali
Antonella
A
Roncarati
Roberta
R
Strocchi
Paola
P
Zaccheo
Damiano
D
D'Adamio
Luciano
L
Tabaton
Massimo
M
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003600:Cytosol / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000473:pathology*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000473:pathology*; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor