Establishing the Relationship Between Alzheimer's Disease and Calcium Movements Within the Cell

Tae-Wan Kim, PhD
Columbia University Medical Center (New York, NY)
Year Awarded:
2000
Grant Duration:
April 1, 2000 to March 31, 2002
Disease:
Alzheimer's Disease
Award Amount:
$190,000
Grant Reference ID:
A2000002
Award Type:
Standard
Award Region:
US Northeastern
Recipient of the 2000 Ruth Salta Junior Investigator Achievement Award from BrightFocus Foundation.
Tae-Wan Kim, PhD

Role of Presenilins in Capacitative Calcium Entry

Details

When the normal intracellular stores of calcium are depleted, a response is triggered inside the cell that leads to the influx of calcium from outside the cell. This process is known as capacitative calcium entry, or CCE. Dr. Tae-Wan Kim has found that mutations in presenilin 1 (PS1) or presenilin 2 (PS2) that cause inherited AD are associated with an impaired CCE response. It has also been found that treating cells with an inhibitor of the CCE response causes an increase in the expression of the protein Ab42. This suggests that the CCE response is coupled with the gamma secretase activity associated with PS1, and that it causes the production of Ab42. Dr. Kim is examining these relationships in more detail to determine whether the reduction of CCE is an early event in AD. He also hopes to determine whether increasing CCE response reduces gamma secretase activity. If it does, this result would raise the possibility that drugs that stimulate CCE could lead to the decreased production of Ab42 and the progression of AD.

Publications

Lee, H.J., Jung, K.M., Huang, Y.Z., Bennett, L.B., Lee, J.S, Mei, L., and Kim, T.W.(2002) Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem. 277(8):6318-6323.  

Sawamura, N., Morishima-Kawashima, M., Waki, H., Kobayashi, K., Kuramochi, T., Frosch, M.P., Ding, K., Ito, M., Kim, T.W., Tanzi, R.E., Oyama, F., Tabira, T., Ando, S., and Ihara, Y. (2000) Mutant presenilin 2 transgenic mice: a large increase in the levels of AB42 is presumably associated with the low-density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin. J Biol. Chem. 275(36):27901-27908.  

Yoo, A.S., Cheng, I., Chung, S., Grenfell, T.Z., Lee, H., Pack-Chung, E., Handler, M., Shen, J., Xia, W., Tesco, G., Saunders, A.J., Ding, K., Frosch, M.P., Tanzi, R.E., and Kim, T.W. (2000) Presenilin-mediated modulation of capacitative calcium entry. Neuron. 27(3):561-572. [Alzforum Recommended Paper][Alzforum Milestone Paper]  

[Book Chapter] Cheng, I., Yoo, A.S., Tanzi, R.E., and Kim, T.W. (2000) Familial Alzheimer's disease-linked mutatnt presenilins attenuate capacitative calcium entry. In: K Iqbal, S.S. Sisodia & B. Winblad, eds. Alzheimer's disease: biology, diagnosis and treatment.
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