Alzheimer's Disease Research - Current Award

	J. Kevin Foskett, Ph.D. University of Pennsylvania Philadelphia, PA Title: IP3R-Presenilin Interaction: Calcium Dysregulation in AD Non-Technical Title: Calcium disruption in Alzheimer's Disease Duration: April 1, 2008 - March 31, 2011 Award Type: Standard Award Amount: $400,000
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.

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 Archiv 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).

Progress Updates:

The broad goal of our proposed studies is to exploit novel insights into the effect of calcium (Ca²⁺) on Alzheimer’s disease (AD). We are exploring the interactions of presenilin (PS) proteins with the inositol trisphosphate receptor (InsP3R), a channel that releases Ca²⁺ from internal stores into the rest of the cell. We previously found that the disease-causing mutant PS proteins cause the channel to be overly active, resulting in excessive Ca²⁺ within cells. We have made substantial progress during this AHAF funding period by extending our research investigations to other mutant, AD-causing proteins in the same PS family, and to cells from AD patients. We have obtained deeper insights into how presenilins cause the Ca²⁺ channel to be over-active. Based on our extended insights, we are now moving our studies into animal models of AD, to determine whether excessive Ca²⁺ is observed in these animals, and if we can reduce the symptoms of AD by subduing the Ca²⁺ channel activity.