TY - JOUR
T1 - Presenilin-mediated modulation of capacitative calcium entry
AU - Yoo, Andrew S.
AU - Cheng, Isaac
AU - Chung, Sungkwon
AU - Grenfell, Tallessyn Z.
AU - Lee, Hanmi
AU - Pack-Chung, Eunju
AU - Handler, Melissa
AU - Shen, Jie
AU - Xia, Weiming
AU - Tesco, Giuseppina
AU - Saunders, Aleister J.
AU - Ding, Kai
AU - Frosch, Matthew P.
AU - Tanzi, Rudolph E.
AU - Kim, Tae Wan
N1 - Funding Information:
We thank T. Rahmati and D. J. Selkoe for Aβ ELISAs, M. Wolfe for the D257A-PS1 construct, K. T. Kim for helpful discussions, G. E. Gibson for critical comments on the manuscript, and T. Tomita, T. Iwatsubo, G. Thinakaran, and S. Sisodia for antibodies. This work was supported by the National Institute on Aging grants AG18026 (T.-W. K.), AG05845 (A. J. S.), and AG15379 (R .E. T.) and grants from the American Health Assistance Foundation (T.-W. K.), Alzheimer's Association (R. E. T.), Partners Healthcare System (T.-W. K.), and Brain Science and Engineering Research Program sponsored by the Korean Ministry of Science and Technology (S. C.). I. C. is a Howard Hughes Medical Institute Medical Student Training Fellow and T.-W. K. is a recipient of the Partners Investigator (Nesson) Award.
PY - 2000
Y1 - 2000
N2 - We studied a novel function of the presenilins (PS1 and PS2) in governing capacitative calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores. Abrogation of functional PS1, by either knocking out PS1 or expressing inactive PS1, markedly potentiated CCE, suggesting a role for PS1 in the modulation of CCE. In contrast, familial Alzheimer's disease (FAD)-linked mutant PS1 or PS2 significantly attenuated CCE and store depletion-activated currents. While inhibition of CCE selectively increased the amyloidogenic amyloid β peptide (Aβ42), increased accumulation of the peptide had no effect on CCE. Thus, reduced CCE is most likely an early cellular event leading to increased Aβ42 generation associated with FAD mutant presenilins. Our data indicate that the CCE pathway is a novel therapeutic target for Alzheimer's disease.
AB - We studied a novel function of the presenilins (PS1 and PS2) in governing capacitative calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores. Abrogation of functional PS1, by either knocking out PS1 or expressing inactive PS1, markedly potentiated CCE, suggesting a role for PS1 in the modulation of CCE. In contrast, familial Alzheimer's disease (FAD)-linked mutant PS1 or PS2 significantly attenuated CCE and store depletion-activated currents. While inhibition of CCE selectively increased the amyloidogenic amyloid β peptide (Aβ42), increased accumulation of the peptide had no effect on CCE. Thus, reduced CCE is most likely an early cellular event leading to increased Aβ42 generation associated with FAD mutant presenilins. Our data indicate that the CCE pathway is a novel therapeutic target for Alzheimer's disease.
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U2 - 10.1016/S0896-6273(00)00066-0
DO - 10.1016/S0896-6273(00)00066-0
M3 - Article
C2 - 11055438
AN - SCOPUS:0033712477
VL - 27
SP - 561
EP - 572
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 3
ER -