Endogenous APP derivatives oppositely modulate apoptosis through an autocrine loop.
We have recently shown that, in rat cerebellar granule cells, apoptosis triggered by KCl deprivation is associated with an amyloidogenic shift in the processing of amyloid precursor protein (APP) resulting in an increase of amyloid beta-protein (A beta) secretion. To further investigate this issue we studied the relationship between secretion of APP metabolites (A beta, APPs) and neuronal degeneration. We postulated that the endogenous products of the APP metabolism may modulate neuronal survival by an autocrine loop. Treatment of cerebellar granule cells with various antibodies raised against different epitopes of APPs and A beta oppositely modulates low potassium apoptotic cell death. Antibodies specific for the N-terminal of A beta (4G8, 6E10, R3659) increased neuronal survival by 30% over controls. On the contrary, treatment of cultures undergoing apoptosis with the monoclonal antibody 22C11 directed against the APP N-terminus reduced neuronal survival by 53%, suggesting that endogenous alpha-APPs contribute to neuronal survival. Moreover low KCl culture medium, conditioned by cerebellar granule cells, attenuated the apoptotic process. This anti-apoptotic effect was abolished by removal of APPs from the conditioned medium. Western blotting of APPs removed from the conditioned medium confirmed the presence of alpha-APPs. These data indicate that APP cleavage products oppositely modulate neuronal survival through an autocrine loop and further strengthen an Alzheimer's disease pathogenetic scheme based on altered metabolism of APP.
Piccini
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Istituto di Neurobiologia, Consiglio Nazionale delle Ricerche, Rome, Italy.
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D016564:Amyloid beta-Protein Precursor / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D019898:Autocrine Communication / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D009474:Neurons / Q000166:cytology*; D009500:Neutralization Tests; D051381:Rats; D017208:Rats, Wistar
D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal