Bax-interacting factor-1 (Bif-1) was originally identified as a pro-apoptotic protein that binds to and activates the cell death protein Bax in response to apoptotic stress. However, the role of Bif-1 in post-mitotic neurons has not been investigated. In contrast to non-neuronal cells, we recently observed that Bif-1 promotes cell survival in neurons. In an attempt to determine if Bif-1 function is relevant to neurodegenerative diseases, we observed that a unique neuron-specific splice variant of the Bif 1 protein is significantly reduced in the brains of sporadic Alzheimer’s disease (AD) patients compared to age-matched non-AD patients. These changes in Bif-1 are also observed in the APPswe/PS1dE9 mouse model of AD. Importantly, the Bif-1-null condition enhanced neuronal cell death caused by DNA damage and Abeta cytotoxicity in culture. Conversely, overexpression of the unique neuron-specific splice variant of Bif-1 conferred significant protection against Abeta-mediated toxicity indicating that Bif-1 is required for normal neuronal function. Moreover, in preliminary studies, we crossed APPswe/PS1dE9 AD mice with Bif-1-null mice and observed that the Bif-1-null condition dramatically increased the accumulation of ß-amyloid plaques coupled with elevated astrocyte activation. We also found that Bif-1 knockout mice developed larger infarcts following ischemic stroke. These findings demonstrate a neuroprotective function for Bif-1 and suggest that loss of Bif-1 may be causally involved in the progression of AD. In this application we propose to create a transgenic mouse line that expresses the neuron-specific form of Bif-1 in a neuron-specific and inducible manner to test the hypothesis that maintenance of Bif-1 expression in neurons can reduce cognitive impairment and neuropathological changes in a mouse model of AD.
Sponsor Award Number