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Volume 17, Number 11,
Issue of June 1, 1997
pp. 4212-4222
Copyright ©1997 Society for Neuroscience
Alzheimer's Presenilin Mutation Sensitizes Neural Cells to
Apoptosis Induced by Trophic Factor Withdrawal and Amyloid
 -Peptide: Involvement of Calcium and Oxyradicals
Received Feb. 12, 1997; revised March 20, 1997; accepted March 25, 1997.
Qing Guo1,
Bryce L. Sopher2,
Katsutoshi Furukawa1,
Dao G. Pham2,
Nic Robinson1,
George M. Martin2, and
Mark P. Mattson1
1 Sanders-Brown Research Center on Aging and Department
of Anatomy and Neurobiology, University of Kentucky, Lexington,
Kentucky 40536, and 2 Department of Pathology, University
of Washington, Seattle, Washington 98195-7470
Most autosomal dominant inherited forms of early onset Alzheimer's
disease (AD) are caused by mutations in the presenilin-1 (PS-1) gene on
chromosome 14. PS-1 is an integral membrane protein with six to nine
membrane-spanning domains and is expressed in neurons throughout the
brain wherein it is localized mainly in endoplasmic reticulum (ER). The
mechanism or mechanisms whereby PS-1 mutations promote neuron
degeneration in AD are unknown. Recent findings suggest links among
deposition of amyloid  -peptide (A), oxidative stress, disruption
of ion homeostasis, and an apoptotic form of neuron death in AD. We now
report that expression of the human PS-1 L286V mutation in PC12 cells
increases their susceptibility to apoptosis induced by trophic factor
withdrawal and A. Increases in oxidative stress and intracellular
calcium levels induced by the apoptotic stimuli were exacerbated
greatly in cells expressing the PS-1 mutation, as compared with control cell lines and lines overexpressing wild-type PS-1. The antiapoptotic gene product Bcl-2 prevented apoptosis after NGF withdrawal from differentiated PC12 cells expressing mutant PS-1. Elevations of [Ca2+]i in response to thapsigargin, an
inhibitor of the ER Ca2+-ATPase, were increased in cells
expressing mutant PS-1, and this adverse effect was abolished in cells
expressing Bcl-2. Antioxidants and blockers of calcium influx and
release from ER protected cells against the adverse consequences of the
PS-1 mutation. By perturbing cellular calcium regulation and promoting
oxidative stress, PS-1 mutations may sensitize neurons to apoptotic
death in AD.
Key words:
Alzheimer's disease;
antioxidant;
bcl-2;
dantrolene;
endoplasmic reticulum;
fura-2;
nerve growth factor
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March 12, 1999;
274(11):
7264 - 7271.
[Abstract]
[Full Text]
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M. P. Mattson and Qing Guo
{blacksquare} REVIEW : The Presenilins
Neuroscientist,
March 1, 1999;
5(2):
112 - 124.
[Abstract]
[PDF]
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C. Choi, J. Y. Park, J. Lee, J.-H. Lim, E.-C. Shin, Y. S. Ahn, C.-H. Kim, S.-J. Kim, J.-D. Kim, I. S. Choi, et al.
Fas Ligand and Fas Are Expressed Constitutively in Human Astrocytes and the Expression Increases with IL-1, IL-6, TNF-{alpha}, or IFN-{gamma}
J. Immunol.,
February 15, 1999;
162(4):
1889 - 1895.
[Abstract]
[Full Text]
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C.-S. Hong, L. Caromile, Y. Nomata, H. Mori, D. E. Bredesen, and E. H. Koo
Contrasting Role of Presenilin-1 and Presenilin-2 in Neuronal Differentiation In Vitro
J. Neurosci.,
January 15, 1999;
19(2):
637 - 643.
[Abstract]
[Full Text]
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E. Jaikaran, G Marcon, L Levesque, P. George-Hyslop, P. Fraser, and A Clark
Localisation of presenilin 2 in human and rodent pancreatic islet beta-cells; Met239Val presenilin 2 variant is not associated with diabetes in man
J. Cell Sci.,
January 7, 1999;
112(13):
2137 - 2144.
[Abstract]
[PDF]
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S. Bursztajn, R. DeSouza, D. L. McPhie, S. A. Berman, J. Shioi, N. K. Robakis, and R. L. Neve
Overexpression in Neurons of Human Presenilin-1 or a Presenilin-1 Familial Alzheimer Disease Mutant Does Not Enhance Apoptosis
J. Neurosci.,
December 1, 1998;
18(23):
9790 - 9799.
[Abstract]
[Full Text]
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A. Takashima, M. Murayama, O. Murayama, T. Kohno, T. Honda, K. Yasutake, N. Nihonmatsu, M. Mercken, H. Yamaguchi, S. Sugihara, et al.
Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau
PNAS,
August 4, 1998;
95(16):
9637 - 9641.
[Abstract]
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J. N. Keller, Q. Guo, F. W. Holtsberg, A. J. Bruce-Keller, and M. P. Mattson
Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-1 Is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production
J. Neurosci.,
June 15, 1998;
18(12):
4439 - 4450.
[Abstract]
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Q. Guo, N. Robinson, and M. P. Mattson
Secreted beta -Amyloid Precursor Protein Counteracts the Proapoptotic Action of Mutant Presenilin-1 by Activation of NF-kappa B and Stabilization of Calcium Homeostasis
J. Biol. Chem.,
May 15, 1998;
273(20):
12341 - 12351.
[Abstract]
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Q. Guo, S. Christakos, N. Robinson, and M. P. Mattson
Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: Reduced oxidative stress and preserved mitochondrial function
PNAS,
March 17, 1998;
95(6):
3227 - 3232.
[Abstract]
[Full Text]
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W. A. Pedersen, Q. Guo, B. K. Hartman, and M. P. Mattson
Nerve Growth Factor-independent Reduction in Choline Acetyltransferase Activity in PC12 Cells Expressing Mutant Presenilin-1
J. Biol. Chem.,
September 5, 1997;
272(36):
22397 - 22400.
[Abstract]
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S. L. Chan, M. Mayne, C. P. Holden, J. D. Geiger, and M. P. Mattson
Presenilin-1 Mutations Increase Levels of Ryanodine Receptors and Calcium Release in PC12 Cells and Cortical Neurons
J. Biol. Chem.,
June 9, 2000;
275(24):
18195 - 18200.
[Abstract]
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I. Schneider, D. Reverse, I. Dewachter, L. Ris, N. Caluwaerts, C. Kuiperi, M. Gilis, H. Geerts, H. Kretzschmar, E. Godaux, et al.
Mutant Presenilins Disturb Neuronal Calcium Homeostasis in the Brain of Transgenic Mice, Decreasing the Threshold for Excitotoxicity and Facilitating Long-term Potentiation
J. Biol. Chem.,
April 6, 2001;
276(15):
11539 - 11544.
[Abstract]
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Q. Guo, J. Xie, X. Chang, and H. Du
Prostate Apoptosis Response-4 Enhances Secretion of Amyloid beta Peptide 1-42 in Human Neuroblastoma IMR-32 Cells by a Caspase-dependent Pathway
J. Biol. Chem.,
May 4, 2001;
276(19):
16040 - 16044.
[Abstract]
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Z. Pan, M. B. Bhat, A.-L. Nieminen, and J. Ma
Synergistic Movements of Ca2+ and Bax in Cells Undergoing Apoptosis
J. Biol. Chem.,
August 17, 2001;
276(34):
32257 - 32263.
[Abstract]
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M. H. Scheinfeld, R. Roncarati, P. Vito, P. A. Lopez, M. Abdallah, and L. D'Adamio
Jun NH2-terminal Kinase (JNK) Interacting Protein 1 (JIP1) Binds the Cytoplasmic Domain of the Alzheimer's beta -Amyloid Precursor Protein (APP)
J. Biol. Chem.,
January 25, 2002;
277(5):
3767 - 3775.
[Abstract]
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Z. Pan, D. Damron, A.-L. Nieminen, M. B. Bhat, and J. Ma
Depletion of Intracellular Ca2+ by Caffeine and Ryanodine Induces Apoptosis of Chinese Hamster Ovary Cells Transfected with Ryanodine Receptor
J. Biol. Chem.,
June 23, 2000;
275(26):
19978 - 19984.
[Abstract]
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