Downstream Regulators B-amyloid Induced Neuronal Death

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DESCRIPTION (provided by applicant): Our overall aim is to determine the molecular mechanisms of beta-amyloid-induced neuronal death. Deposition of insoluble Abeta, together with tangle formation and neuronal loss, are hallmarks of Alzheimer's disease. Recent studies show that increased Abeta induces synaptotoxicity, a parameter which correlates with cognitive decline in AD. Evidence from our work and from other laboratories shows that insoluble Abeta induces apoptosis in cultured neurons. The Abeta-mediated death pathway has many similarities to the trophic factor deprivation (TFD) mediated death pathway. These include induction of c-fos and c-jun, use of cell cycle components, activation of the JNK cascade, and protection by bcl-2. We have clearly demonstrated that caspase-2 is necessary for Abeta as well as for TFD mediated death and that although there is parallel activation of caspase-3 it is not sufficient to induce death. However, data obtained from caspase-2 null mice indicate that the death pathways of these two stimuli are not identical: cultured sympathetic neurons from these mice are protected from Abeta but not from TFD. We propose the hypothesis that Abeta and TFD both execute death via a caspase-2 mediated pathway but that the relative expression of caspase regulators (IAPs and Diablo/SMAC) determines different alternative pathways for Abeta and TFD. We additionally propose the hypothesis that JNK activation leads to induction of Fas and recruitment of RAIDD activating caspase-2. By contrasting and comparing the mechanisms employed by these two death stimuli we can further dissect the Abeta-mediated death pathway. We will examine these hypotheses with the following specific aims: 1. To determine which caspases are activated (processed) during Abeta and TFD mediated death and which caspases can execute Abeta and TFD induced death. 2. To determine whether there is differential expression and regulation of MIAP3 or Diablo after Abeta or TFD. 3. To determine whether activation of the JNK cascade leads to caspase-2 activation. 4. To determine whether the molecular components of the Abeta death pathway, identified in the preceding Aims, are altered in a mouse model of AD and/or in human AD brain.