Transsynaptic degeneration of corticocortical pathways is a central mechanism for the propagation of pathology an cell death in systems degenertions involving the cerebral cortex, including Alzheimer's disease. We propose that this type of degeneration may represent an appropriate and realistic target of pathogenic events in these disorders. In the present proposal, we focus on a very reliable in vivo model of transsynaptic cortical degeneration that we have recently developed, i.e., the apoptotic death of pyramidal neurons in the piriform cortex after their disconnection from the olfactory bulb. We investigate specific cellular/molecular events subsequent to bulbotomy such as excitotoxic-type alterations of distal dendrites of deafferented neurons, NOS/No signaling impacting on these neurons; and cell cycle and death genes such as Cyclin D1 and bax. To confirm data from anatomical/expression experiments, we use a number of pharmacological interventions, including: protein synthesis inhibitors that influence apoptosis but not excitotoxicity; small molecules that target glutamate synthesis, release and binding to block excitotoxicity and, in so doing, ameliorate of abolish apoptotic cortical cell death; NOS inhibitors/NO scavengers; cyclin-dependent kinase inhibitors to block cyclin signaling; and caspase inhibitors. We also use mice with genetic advantages that prevent apoptotic neuronal death (e.g., nNOS nulls, bax nulls, ICE-dominant negative Tgs). We expect that these carefully controlled investigations will shed light on critical intermediate mechanisms of cortical degenerations and will suggest clinically advantageous methods to treat these disorders.
