Bif-1 therapy for cognitive impairment and neuropathology in AD

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.

Principal Investigator(s)
Research Lab
Award Info

Sponsor Award Number 

A2014237S