P75 and Trk involvement in the activation of amyloidogenesis following NGF removal

P75 AND TRK INVOLVEMENT IN THE ACTIVATION OF AMYLOIDOGENESIS FOLLOWING NGF REMOVAL C. Matrone, R. Marolda, M.T. Ciotti, S. Ciaffrè, D. Mercanti, P. Calissano Centro Nazionale delle Ricerche, Neuroscience and Molecular Medicine Institute, Roma, Italy We report that interruption of NGF signaling from cultured 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? aggregates partly released into the culture medium. The released pool of A? induces an increase of APP and PS1 holoprotein levels and cause the death of healthy neurons by creating a sort of feedforward toxic loop. A? overproduction, following NGF withdrawal, induces TrkA receptor hyperphosphorylation (TrKA-pp) and AKT and IP3 signal interruption. Moreover, soon after NGF removal, TrkA-pp appears associated with p75 C-terminal ectodomain to form a molecular complex. All these events are prevented by anti A? antibodies or by ? and ? secretase inhibitors pointing to A? as the trigger and possibly upstream cause of them. Together with evidences supported by Amadoro et al (see poster of this meeting) these studies prospect the NGF dependent hyppocampal cultures as an ideal system to dissect in vitro the crucial steps of the "Alzheimer's molecular syndrome" and point to a lack supply of NGF or of other neurotrophin(s) as possible causes in the onset of this disease