NGF and BDNF signaling control amyloidogenic route and Aβ production in hippocampal neurons

Here, we report that interruption of NGF or BDNF signaling in hippocampal neurons rapidly activates the amyloidogenic pathway and causes neuronal apoptotic death. These events are associated with an early intracellular accumulation of PS1 N-terminal catalytic subunits and of APP C-terminal fragments and a progressive accumulation of intra- and extracellular A beta aggregates partly released into the culture medium. The released pool of A beta induces an increase of APP and PS1 holoprotein levels, creating a feed-forward toxic loop that might also cause the death of healthy neurons. These events are mimicked by exogenously added A beta and are prevented by exposure to beta- and gamma-secretase inhibitors and by antibodies directed against A beta peptides. The same cultured neurons deprived of serum die, but APP and PS1 overexpression does not occur, A beta production is undetectable, and cell death is not inhibited by anti-A beta antibodies, suggesting that hippocampal amyloidogenesis is not a simple consequence of an apoptotic trigger. but is due to interruption of neurotrophic signaling.