Restoring a Novel Multifunctional Protein in Neurons to Enhance Cognitive Function in Alzheimer’s Disease

Richard Morrison, PhD
University of Washington School of Medicine (Seattle, WA)
Year Awarded:
Grant Duration:
July 1, 2014 to June 30, 2017
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northwestern

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


We have identified a protein with a unique protective function in nerve cells that is lost in the brains of patients with Alzheimer’s disease. In the past, we have studied this protein in mice engineered to show symptoms of Alzheimer’s disease and the results suggest that the absence of this protein may make the disease worse. We would like to determine if we can improve cognitive function in patients with Alzheimer’s disease by restoring the expression of this protein. We will test this possibility by developing a method to restore this protein in the nerve cells in a mouse model of Alzheimer’s disease, and we will determine if cognitive abilities improve.


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.

About the Researcher

Richard S. Morrison obtained his Bachelor of Science degree in biological sciences from the University of Southern California in Los Angeles. He pursued a PhD in cell biology and anatomy at the University of California, Los Angeles, where he studied growth factor function in the central nervous system. He completed postdoctoral studies in biological chemistry at the University of California, Irvine, where he discovered a novel function for the fibroblast growth factor protein in supporting neuronal survival. After taking several positions around the country, he arrived at his present position at the University of Washington in 1994. He is presently the Staatz Professor of neurological surgery and director of the Neuroproteomics Center. Dr. Morrison’s research focus is related to understanding the molecular responses induced in brain cells in response to nervous system injury and disease.