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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (35), p.13139-13144
• Main Authors: Matrone, Carmela, Ciotti, Maria Teresa, Mercanti, Delio, Marolda, Roberta, Calissano, Pietro
• Format: Article
• Language: English
• Subjects: Alzheimers disease; Antibodies; Apoptosis; Biological Sciences; Brain; Cell death; Cell lines; Neurons; Percentages; Proteins; Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0806133105

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 Aβ aggregates partly released into the culture medium. The released pool of Aβ 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 Aβ and are prevented by exposure to β- and γ-secretase inhibitors and by antibodies directed against Aβ peptides. The same cultured neurons deprived of serum die, but APP and PS1 overexpression does not occur, Aβ production is undetectable, and cell death is not inhibited by anti-Aβ antibodies, suggesting that hippocampal amyloidogenesis is not a simple consequence of an apoptotic trigger but is due to interruption of neurotrophic signaling.