p75 and TRKA activation following amyloidogenesis induced by NGF removal

p75 and TRKA activation following amyloidogenesis induced by NGF removal C. Matrone (1), R. Marolda (1),S. Ciafrè (1), M.T. Ciotti (1), D. Mercanti(1), P. Calissano(2). (1)Centro Nazionale delle Ricerche, Neuroscience and Molecular Medicine Institute (INMM) (2) European Brain Research Institute(EBRI), Via Fosso del Fiorano 64, 00143 Roma, Italy Alzheimer's Disease (AD) is the most relevant and frequent form of senile dementia, characterized by a progressive decline in cognitive functions. Several evidences link AD to an impaired NGF signaling. 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 Abeta aggregates partly released into the culture medium. The released pool of Abeta induces an increase of APP and PS1 holoprotein levels and causes death of healthy neurons by creating a sort of feed forward toxic loop which is prevented by anti Abeta antibodies. The increased Abeta peptide production induces an anomalous TrkA phosphorylation followed by activation of PLCgamma pathway and neuronal death. After NGF removal, phosphoTrkA appears associated with p75 C-terminal ectodomain to form a molecular complex also including Abeta peptides and PS1 N-terminus subunit. The inhibition of APP processing or partial silencing of TrkA and/or p75 receptor protect neurons from death pointing to Abeta as the trigger and upstream cause of these events and suggesting a close sterical association between the NGF receptor system and the APP processing pathway. These studies prospect the NGF dependent hyppocampal cultures as a model to induce and analyze an in vitro "Alzheimer's like molecular syndrome" and point to an impairment of NGF signal as a possible cause of AD. Keywords: Alzheimer Disease, NGF receptors, amyloidogenesis, apoptosis, neurodegeneration Presenting author: Carmela Matrone