Gwenn A. Garden, M.D., Ph.D.

gagarden@u.washington.edu
Associate Professor, Department of Neurology

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Our laboratory is currently focusing on the following specific projects:

1. Neurons exposed to the HIV-gp120 coat protein undergo apoptosis when cultured in the presence of microglia (CNS macrophages). Transgenic expression of HIV-gp120 in the brain results in synaptic loss and dendritic simplification. Microglial activation is required for the toxicity of exogenous gp120 suggesting that cytokines play an important role in gp120 induced neuronal apoptosis. Cytokines such as TNF-a can directly initiate the apoptotic cascade through activation of caspase enzymes. Additionally, inflammatory cytokines alter glutamate homeostasis and promote the accumulation of amino acid metabolites capable of over stimulating glutamate receptors. The resulting "excitotoxicity" can also promote caspase enzyme activation. We are studying the caspase enzyme cascades induced by gp120 exposure in cultured neurons, astrocytes and microglia as well as in gp120 transgenic mice.
2. Do proteins involved in apoptosis have an additional role in modulating neuronal architecture? Caspases are regulated by multiple signal transduction pathways. Those pathways overlap with signals involved in synaptic plasticity. Cytoskeletal proteins (including actin, spectrin and tau) undergo caspase enzyme cleavage. Caspase enzyme activity has been observed in synaptosomal preparations and antigenic localization of these enzymes has been demonstrated in both axons and dendrites. We hypothesize that this family of enzymes may participate in a physiologic reorganization of the neuronal cytoskeleton in addition to their function in apoptosis. We employ well-described models of axon and dendrite injury and reorganization to study caspase involvement in these processes.
3. We are attempting to study the interaction between apoptotic neurons and microglia. If microglia are stimulated to release neurotoxic compounds by the presence of injured axons and dendrites, a vicious cycle can be initiated by mild injury to the CNS. This interaction could contribute to several neurodegenerative diseases. We are studying this interaction in vitro and in several disease models including ALS, HIV dementia and several genetic neurodegenerative diseases.