Neuronal apoptosis is accompanied by amyloid ?-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 ?-protein (A?) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280-290% increase of respectively intracellular and secreted A? occurred, in spite of a 20% reduction of cellular metabolism and an unchanged A?PP expression. The increased intracellular A? reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus of A?PP, but only partially rescued A? overproduction caused by staurosporine treatment. Our findings suggest that PCD fosters the physiological pathways of A? 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?PP processing during PCD.