Calcium disruption in Alzheimer's Disease

J. Kevin Foskett, PhD
University of Pennsylvania (Philadelphia, PA)
Year Awarded:
2008
Grant Duration:
April 1, 2008 to March 31, 2011
Disease:
Alzheimer's Disease
Award Amount:
$400,000
Grant Reference ID:
A2008137
Award Type:
Standard
Award Region:
US Northeastern
J. Kevin Foskett, PhD

IP3R-Presenilin Interaction: Calcium Dysregulation in AD

Summary

This study is designed to test how presenilin interacts with calcium signaling proteins, resulting in changes to the presenilin function. The study will also examine how altered calcium signaling in turn affects other cell functions. These studies should provide new insights into the molecular mechanisms of AD and into the development of novel targets for therapeutic interventions.

Details

Alzheimer's disease (AD) is a common form of dementia involving slowly developing degeneration of neurons in the brain. The causes of AD are still not clear, but mutations in some proteins that result in early-onset cases of the disease provide clues. One of these proteins, presenilin, causes the amount of calcium in cells to be abnormally regulated. Because calcium regulates many brain functions, this abnormality may be a key part of the disease. We have discovered a mechanism whereby mutant forms of presenilin that cause AD alter the function of an important protein that regulates calcium signals in cells. Calcium in cells is precisely regulated, because it is toxic if its concentration is too high. Chronic abnormal calcium regulation as a result of mutations in presenilin may therefore cause cellular toxicity that leads to cell death. We plan to study how presenilin interacts with this important calcium signaling protein to alter its function, and how altered calcium signaling in turn affects cell functions. These studies should provide new insights into the molecular mechanisms of AD and into the development of novel targets for therapeutic interventions.

Research Updates

Changes to the presenilin gene can cause familial Alzheimer's disease (FAD), an early-onset form of Alzheimer's disease (AD). Dr. Kevin Foskett and collaborators discovered that mutant presenilin proteins can interact with and stimulate the activity of an important protein that regulates calcium signals in cells, called InsP3R. This InsP3R stimulation results in abnormally exaggerated calcium signals in cells that, in turn, stimulates beta-amyloid protein processing, an important feature for progression to AD. These signals also enhance the production of toxic oxygen radicals, a feature of both AD and aging.  In addition, Dr. Foskett showed that the effects of mutant presenilin proteins on calcium signaling mirrored what was previously known about FAD genetics. These effects were demonstrated both in cells derived from individuals with FAD and in brain neurons from mice that express the human mutant presenilin. Thus, Dr. Foskett's discoveries provide new insights into what causes Alzheimer's disease and could lead to the development of new targets for future treatments.

Publications

Cheung, K.H., D. Shineman, M. Muller, C. Cardenas, L. Mei, J. Yang, T., Tomita, T. Iwatsubo, V. M.-Y. Lee and J. K. Foskett. 2008. Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58:871-883. [PMCID: PMC2495086]  

This study established that FAD mutant presenilins impinged on the activity of the InsP3R Ca2+ release channel that affected amyloid production Cheung, K.-H., L. Mei, D.-O. D. Mak, I. Hayashi, T. Iwatsubo and J. K. Foskett. 2010. Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Science Signaling 3:ra22, 1-10.  

This study extended the observations in (1) to show that the mechanism operates for many FAD causing presenilins, and in human FAD patient cells and in neurons from transgenic AD mice. Foskett, J.K. 2010. Inositol trisphosphate receptor Ca2+ release channels in neurological diseases. Pflugers Archive European J. Physiol. (in press)  

This is a review article that summarizes the data from two earlier studies. Mu:ller, M. K.-H. Cheung and J.K. Foskett. 2010. Enhanced ROS generation mediated by Alzheimer's disease presenilin regulation of InsP3R Ca2+ signaling. Antioxidants and Redox Signaling (in press). Mu:ller, M. K.-H. Cheung, L. Mei, J. Molgo, C. Cardenas and J. K. Foskett. Constitutive CREB activation by Alzheimer's disease presenilin-driven InsP3R Ca2+ signaling. (submitted to J. Neurosci).

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