Bif-1 Therapy for Cognitive Impairment and Neuropathology in Alzheimer’s Disease

Project Summary

The goal of our project is to enhance cognitive function and reduce cell damage in Alzheimer’s disease (AD) by restoring expression of a novel multifunctional protein in neurons that is lost during the progression of AD.

We have identified a multi-functional protein (Bif-1) that is lost in human AD brain and in a mouse model of AD. We are developing a new mouse model that allows us to selectively restore the expression of this protein in cells of the central nervous system. This novel mouse model can then be crossed with mice expressing mutant human AD genes in order to determine if restoration of this protein can improve cognitive impairment and the pathological changes observe in mouse models of AD. Using our mouse model, we will be able to selectively express this important protein in any cell type and at any time during the course of the disease, in order to determine where it should be expressed and how far along in the disease process could it be expressed to still block or reverse symptoms of AD.

The major innovation of our project lies in developing a novel mouse model to study a newly identified neuroprotective function for the Bif-1 protein in neurons. This protein has not previously been associated with any human neurodegenerative disease and our recent studies demonstrate that this protein is required to support neuronal survival in response to cell stress, such as Abeta toxicity. Our studies are the first to demonstrate that this neuroprotective protein is significantly reduced in the parietal cortex and in synaptosomes of sporadic AD patients compared to age-matched non-AD patients. By developing a mouse that facilitates selective restoration of this protein in neurons in AD mice, our studies may identify a novel treatment for improving cognitive function and mitigating neuropathological changes during the progression of AD. As Bif-1 is a multi-functional protein involved in apoptosis, autophagy and mitochondrial dynamics, this mouse will be invaluable to other investigators studying these processes in AD.

The major foreseeable benefits of our work are to determine whether restoring Bif-1 expression in neurons provides a clinically relevant target for enhancing cognitive function, blocking neuropathological changes and sustaining energy production in nerve cells during AD progression. This multifunctional protein will provide researchers in the field with a tool for investigating different aspects of AD development and progression.