Role of a Stress Kinase in AD Pathogenesis
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.
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.
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 substantia 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.