Role of a Stress Kinase in AD Pathogenesis

Narayan Bhat, PhD

Medical University of South Carolina (Charleston, SC, United States)

Year Awarded:

2011

Grant Duration:

July 1, 2011 to June 30, 2015

Disease:

Alzheimer's Disease

Award Amount:

$399,873

Grant Reference ID:

A2011081

Award Type:

Standard

Award Region:

US Southeastern

Summary

The project investigates the role of a key cell signaling pathway commonly involved in cell stress and inflammatory responses i.e., p38 MAP kinase in multiple pathogenic processes of Alzheimer's disease (AD) including neuroinflammation, tau phosphorylation, amyloid deposition and synaptic dysfunction. The approach uses a genetic conditional knockout strategy to cell-specifically delete the kinase in microglia and forebrain neurons in a mouse model of AD. The outcome will provide mechanistic insight into AD-associated pathogenic processes and define the signaling pathway as a versatile treatment target for AD.

Details

The protein called “p38 MAP kinase” is important for many functions in the body, and problems with this protein can cause inflammation and interrupt nerve cell communication in Alzheimer's disease. Dr. Narayan Bhat and collaborators plan to create and study a new mouse model of Alzheimer's. To make this model, they will change the p38 MAP kinase proteins in two parts of the brain, namely in immune cells called microglia, and at the points where the nerve cells communicate, called synapses. The changes in microglia, synapses and overall brain health will be monitored by state‐of‐the‐art techniques, including labeling cells with a special dye and examining them under a special microscope. Information obtained from this study may help to direct future drug therapies.

Research Updates

The project was designed to investigate the role of a key cell signaling (p38 MAP kinase) pathway commonly involved in cell stress and inflammatory responses in Alzheimer's disease (AD) pathology, including brain inflammation, tau protein phosphorylation, amyloid deposits, and loss of communication between nerve cells. Dr. Bhat’s team has generated the first batch of transgenic AD mice in which the p38 MAP kinase gene was specifically deleted from microglia, the brain immune cells, and forebrain neurons. Currently, these mice are being analyzed to confirm the knockout phenotypes. . Once confirmed, these mice will be given various biochemical, histological, and functional tests of AD-like changes, as proposed in the project. The outcome will potentially provide mechanistic insight into AD-associated pathogenic processes and define the p38 MAP kinase signaling pathway as a versatile treatment target for AD.

About the Researcher

Dr. Bhat is a professor in the Department of Neurosciences at the Medical University of South Carolina (MUSC) in Charleston. The Bhat lab has a longstanding research interest in the general area of glial cell function in brain development and disease. A specific area of current focus is on gliamediated neuroinflammation as it relates to the pathogenesis/progression of neurodegenerative diseases, in particular, Alzheimer's disease (AD). The specific approach targets the signal transduction mechanisms that regulate glial cell responses with the intent of developing signal transduction-based interventions anti-inflammatory and immunemodulatory treatment strategies. A related research approach currently pursued is a link between metabolic disorders (i.e., diabetes, atherosclerosis, etc.) and AD development focusing on convergent mechanisms and risk factors including dietary lifestyle.

Publications

Ann-Charlotte Granholm, Vandana Zaman, Jennifer Godbee, Michael Smith, Riad Ramadan, Claudia Umphlet, Patrick Randall, Narayan R. Bhat, Baerbel Rohrer, Lawrence D. Middaugh and Heather A Boger. (2011) Prenatal LPS increases inflammation in the subnstantia nigra of gdnf heterozygous mice. Brain Pathology 21, 330-48.

Kumar Sambamurti, Nigel H. Greig, Tadanobu Utsuki, Eliza L. Barnwell, Ekta Sharma, Cheryl Mazell, Narayan R. Bhat, Mark S. Kindy, Debomoy K. Lahiri, Miguel A Pappolla. (2011) Targets for AD treatment: Conflicting messages from -secretase inhibitors. J. Neurochem. 117, 359-74.

Jin Yu, Marco Gattoni-Celli, Hong Zhu, Narayan R. Bhat, Kumar Sambamurti, Sebastiano Gattoni-Celli, and Mark Kindy. (2011) Vitamin D3-Enriched Diet Correlates with a Decrease of Amyloid Plaques in the Brain of APP Transgenic Mice. J. Alzh Dis. 25(2):295-307, 2011.

Summary

Details

Research Updates

About the Researcher

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