Johns Hopkins Medicine

Alzheimer's Disease Research Center

Transynaptic cortical apoptosis mechanisms and therapy

Principal Investigator: Vassilis Koliatsos, M.D.

Transsynaptic degeneration of corticocorticol pathways is a central mechanism for the propagation of pathology and cell death in systems degenerations involving the cerebral cortex, including Alzheimer's Disease. We propose that this type of degernation may represent an appropriate and realistic target of treatment with small molecules, regardless of the nature of the heterogeneous and largely unknown initial pathogenic evens in these disorders. In the present proposal. We focus on a very reliable in vivo model of transynaptic cortical degeneration that we have recently developed, i.e., the apoptic 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 excitottoxic-type alteration of distal dendrites of deafferented neurons and changes in immediate early genes or cell cycle and death genes known to be involved in bulbotom-induced apoptosis based on our preliminary studies (e.g., c-hun, cyclin D1, bax). Upon the completion of this work, we will extent our investigations to novel genes signaling distinct steps of the apoptotic process by using gene expression profiling and subtraction hybridization. To confirm data from anatomical/expression experiments, we use a number of pharmacological interventions, including: protein synthesis inhibitors that influence apoptosis but not excitotoxicity and, in so doing, ameliorate or abolish apoptotic cortical cell death; c-jun cascade blockers and cyclin-dependent kinase inhibitors to block immediate early gene cyclin signaling. We also use mice wit genetic advantages that prevent apoptotic neuronal death (e.g., bcl-2 overexpressors, ICE-dominant negative mutants, or bax nulls). 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.

For more information, please contact Vassilis Koliatsos, MD, at (410) 502-5172 or koliat@jhmi.edu.