Endogenous APP derivatives oppositely modulate apoptosis through an autocrine loop

We have recently shown that, in rat cerebellar granule cells, apoptosis tri ggered by KCl deprivation is associated with an amyloidogenic shift in the processing of amyloid precursor protein (APP) resulting in an increase of a myloid beta-protein (A beta) secretion. To further investigate this issue w e studied the relationship between secretion of APP metabolites (A beta, AP Ps) and neuronal degeneration. We postulated that the endogenous products o f the APP metabolism may modulate neuronal survival by an autocrine loop. T reatment of cerebellar granule cells with various antibodies raised against different epitopes of APPs and A beta oppositely modulates low potassium a poptotic cell death. Antibodies specific for the N-terminal of A beta (4G8, 6E10, R3659) increased neuronal survival by 30% over controls. On the cont rary, treatment of cultures undergoing apoptosis with the monoclonal antibo dy 22C11 directed against the APP N-terminus reduced neuronal survival by 5 3%, suggesting that endogenous alpha-APPs contribute to neuronal survival. Moreover low KCl culture medium, conditioned by cerebellar granule cells, a ttenuated the apoptotic process. This anti-apoptotic effect was abolished b y removal of APPs from the conditioned medium. Western blotting of APPs rem oved from the conditioned medium confirmed the presence of alpha-APPs. Thes e data indicate that APP cleavage products oppositely modulate neuronal sur vival through an autocrine loop and further strengthen an Alzheimer's disea se pathogenetic scheme based on altered metabolism of APP. NeuroReport 11:1 375-1379 (C) 2000 Lippincott Williams & Wilkins.