NGF and BDNF signaling control amyloidogenic route and Abeta 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 Abeta aggregates partly released into the culture medium. The released pool of Abeta 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 Abeta and are prevented by exposure to beta- and gamma-secretase inhibitors and by antibodies directed against Abeta peptides. The same cultured neurons deprived of serum die, but APP and PS1 overexpression does not occur, Abeta production is undetectable, and cell death is not inhibited by anti-Abeta antibodies, suggesting that hippocampal amyloidogenesis is not a simple consequence of an apoptotic trigger but is due to interruption of neurotrophic signaling.
Matrone
Carmela
C
Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
Ciotti
Maria Teresa
MT
Mercanti
Delio
D
Marolda
Roberta
R
Calissano
Pietro
P
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002457:Cell Extracts; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D044967:Serum; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D002457:Cell Extracts; D004791:Enzyme Inhibitors; D020932:Nerve Growth Factor