Affiliations: [a] Institute of Human Anatomy, Department of Experimental Medicine, University of Genova, Italy | [b] T Cell Apoptosis Unit, Laboratory of Cellular and Molecular Immunology, NIAID, National Institute of Health, Bethesda, USA | [c] INFM and Department of Physics, University of Genova, Italy | [d] Institute of General Pathology, Department of Experimental Medicine, University of Genova, Italy | [e] Department of Neuroscience, University of Genova, Italy | [f] Department of Microbiology and Immunology, Albert Einstein College of Medicine, NY, USA | [g] Department of Experimental Medicine, University of Bologna, Italy
Correspondence:
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Department of Neuroscience, University of Genova, Via De Toni, 5 16132 Genova, Italy. Tel.: +39 10 3537064; E-mail: mtabaton@neurologia.unige.it.
Abstract: 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 β-protein (Aβ) production in a model of neuronal PCD, induced by staurosporine in a murine neuroblastoma cell line. When PCD was induced, a 280–290% secreted Aβ occurred, in spite of a 20% metabolism and an unchanged AβPP expression. The increased intracellular Aβ reactivity largely colocalized with a marker of ER. Inhibition of caspases blocked the cleavage at the C-terminus ofβPP, but only partially rescued Aβ overproduction caused by staurosporine treatment. Our findings suggest that PCD fosters the physiological pathways of Aβ 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 AβPP processing during PCD.
