Accumulating evidence demonstrates that mitochondrial dysfunction is both associated with and causally related to neurodegeneration observed in response to injury and diseases affecting the brain. While disturbances in energy metabolism and ATP production have received significant attention, abnormalities are also being found in the regulation of mitochondrial dynamics which involves the processes of fusion and fission (fragmentation) affecting the shape and size of mitochondria. Importantly, mitochondrial fusion and fission are directly involved in ensuring their proper distribution, transport, and turnover. Considering how vital it is for neurons to have healthy mitochondria positioned at sites of energy demand, it is not difficult to imagine that genetic or epigenetic modifications that impair the regulation of mitochondrial fission and fusion could adversely affect neuronal connectivity, function and viability. We recently determined that neurons express two alternatively spliced forms of a mitochondrial fission regulating protein, Bif-1 (Bif-1b/c). Our preliminary data demonstrates that Bif-1b/c is lost in neurons in the penumbra (cerebral cortex) of mice subjected to middle cerebral artery occlusion (MCAO, stroke model). Importantly, the Bif-1-null condition enhanced neuronal cell death caused by MCAO, and DNA damage and Abeta cytotoxicity in culture. Conversely, Bif-1c overexpression confers significant protection against Abeta-mediated toxicity indicating that Bif-1 is required for normal neuronal function. The Bif-1b/c protein is significantly reduced in the parietal cortex (affected area) and in synaptosomes of sporadic Alzheimer's disease (AD) patients compared to aged matched non-AD patients. These changes in Bif-1b/c are also observed in the APPswe/PS1dE9 mouse AD model and in primary cortical neurons following addition of the toxic Abeta peptide. Moreover, in preliminary studies, Bif-1-null mice displayed significant cognitive impairment at one year of age and knockout of the Bif-1 homologue (endoB) in drosophila enhanced the toxicity of the toxic Abeta42 peptide based on an eye phenotype, but had no effect on flies expressing the non-toxic Abeta40 peptide. These findings demonstrate a potential neuroprotective function of Bif-1 and suggest that mitochondrial dysfunction associated with ischemic damage and AD may be due to reduced expression of Bif-1b/c. We propose to test the hypothesis that restoration of Bif-1c expression in neurons in an inducible transgenic mouse promotes neuronal survival, retention of mitochondrial integrity and enhances cognitive function in response to stroke and in a mouse model of AD. These studies will determine if Bif-1c has therapeutic actions for reducing injury and disease-induced damage.
Alterations in mitochondrial fission and fusion have been observed in a variety of human neurodegenerative diseases and in response to brain injury, suggesting that abnormalities in mitochondrial dynamics may underlie the loss of function seen in these conditions. Utilizing a novel mouse model we hope to develop, we will assess whether an uncharacterized mitochondrial protein that is neuroprotective in cultured neurons against amyloid toxicity confers protection against stroke and damage associated with a mouse model of Alzheimer's disease when overexpressed in neurons. Characterizing abnormalities in the pathways that regulate mitochondrial function and energy production in brain disease and injury will provide potential new targets for mitigating or blocking the cognitive dysfunction associated with brain disease and injury.