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Alzheimer's Disease Research
Completed Award

Dr. Masuo Ohno

Masuo Ohno, Ph.D.

Research Foundation for Mental Hygiene, Inc. at IBR
Orangeburg, NY, United States

Title: eIF2a Kinase GCN2 as a Target for Alzheimer's Therapy
Non-Technical Title: Exploring a Novel Therapeutic Approach for Alzheimer's Disease

Duration: July 1, 2011 - June 30, 2013
Award Type: Pilot
Award Amount: $150,000

Summary:

No treatment is currently available to slow or stop the deterioration of brain cells in Alzheimer's disease (AD), the most common cause of dementia in the elderly. The proposed study will test genetically engineered mouse models, which are expected to block the detrimental beta-secretase-elevating pathway and restore the memory-facilitating CREB function in AD. Our research has important implications for the development of a novel therapeutic approach to halt AD progression and improve synaptic and memory deficits associated with this devastating neurodegenerative disorder.

Details:

Changes in the activity of specific brain proteins lead to an increase in beta-amyloid protein, cell death, and loss of memory in Alzheimer's disease. Dr. Masuo Ohno and colleagues are looking at three protein “players” that increase the levels of beta-amyloid expression, including GCN2, eIF2alpha, and BACE1. The GCN2 protein adds a special chemical group, called a “phosphate,” to the eIF2alpha protein. This changed eIF2alpha then elevates BACE1, a key enzyme responsible for beta-amyloid production. The changed eIF2alpha also suppresses the activity of the CREB protein. CREB helps memories to form, so reducing its activity is bad news for the brain. To break this dual harmful cycle, they will remove the GCN2 gene from mice with Alzheimer's disease so that a phosphate won't be added to eIF2alpha and, therefore, won't elevate BACE1 or suppress CREB. Stopping the BACE1 elevation and the loss of CREB activity could improve the memories of these mice. Their discoveries will help to understand the key chemical changes that happen as Alzheimer's disease progresses, and could lead to new possibilities for disease-modifying drugs.

Progress Updates:

A growing body of evidence indicates that elevation of beta-secretase BACE1, a key enzyme responsible for the production of harmful beta-amyloid (Abeta), occurs in Alzheimer's disease (AD) and contributes to disease progression. Meanwhile, the activity of CREB, a signaling protein that allows brain cells to memorize daily events, is reduced in AD. During the past several years, it has increasingly become apparent that a chemical reaction called "phosphorylation" on the protein eIF2alpha may play a role in inducing both BACE1 elevation and CREB dysfunction. However, the mechanism triggering these dual deleterious changes in brains suffering from AD remains unknown.

To address this question, Dr. Ohno’s team reduced or completely removed the genes of candidate proteins that may cause eIF2alpha phosphorylation in mice. In the past year, the team’s proposed experiments have demonstrated that genetic manipulations of these signaling pathways upstream to eIF2alpha phosphorylation dramatically impact BACE1 expression and Abeta accumulation in a mouse model of AD. The team is currently determining which type of enzyme that phosphorylates the eIF2alpha protein may be the most crucial for mediating BACE1 elevation and/or CREB deficiency in AD. If successful, this will be an initial step toward the validation of the eIF2alpha pathway as a novel disease-modifying therapeutic target to treat AD and memory impairments.

Investigator Biography:

Dr. Masuo Ohno is a research scientist at Nathan Kline Institute and also serves as associate professor, Department of Psychiatry at NYU Langone Medical Center. He has previously held faculty positions at the Physiology Department of Northwestern University's Feinberg School of Medicine, and earned his Ph.D. from Kyushu University in Japan. Ohno's laboratory focuses on the Alzheimer's beta-secretase enzyme called BACE1, which initiates the production of neurotoxic beta-amyloid from its parent molecule APP. His research team applies multidisciplinary analyses, ranging from molecular to behavioral levels, to various genetically engineered mouse models, aimed at the development of disease-modifying therapeutic interventions to treat Alzheimer's disease and memory deficits.

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