 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
Previous Article | Next Article
The Journal of Neuroscience, February 15, 2000, 20(4):1358-1364
Presenilin-1 Mutation Increases Neuronal Vulnerability to Focal Ischemia In Vivo and to Hypoxia and Glucose Deprivation in Cell Culture: Involvement of Perturbed Calcium Homeostasis
Mark P. Mattson1, 3, Haiyan Zhu1, Jin Yu1, 2, 4, and Mark S. Kindy1, 2, 4 1 Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, and 2 Department of Biochemistry, University of Kentucky, Lexington, Kentucky 40536, 3 Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224, and 4 Veterans Affairs Medical Center, Lexington, Kentucky 40506
Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Studies of cultured neural cells suggest that PS1 mutations result in perturbed cellular calcium homeostasis and may thereby render neurons vulnerable to apoptosis. In light of evidence that metabolic impairment plays a role in AD, that cerebral ischemia may be a risk factor for AD, and that individuals with AD have increased morbidity and mortality after stroke, we examined the impact of a PS1 mutation on neuronal vulnerability to ischemic injury. We report that the extent of brain injury after focal cerebral ischemia reperfusion is increased, and behavioral outcome is worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured cortical neurons from PS1 mutant mice exhibit increased vulnerability to glucose deprivation and chemical hypoxia compared to their wild-type counterparts. Calcium imaging studies demonstrated enhanced elevation of intracellular calcium levels after glucose deprivation and chemical hypoxia in neurons from PS1 mutant mice. Agents that block calcium release from IP3- and ryanodine-sensitive stores (xestospongin and dantrolene, respectively) protected against the endangering action of the PS1 mutation. Our data suggest that presenilin mutations may promote neuronal degeneration in AD by increasing the sensitivity of neurons to age-related ischemia-like conditions. The data further suggest that drugs that stabilize endoplasmic reticulum calcium homeostasis may prove effective in suppressing the neurodegenerative process in AD patients.
Key words: Alzheimer's disease; dantrolene; endoplasmic reticulum; knock-in; stroke; transgenic
Copyright © 2000 Society for Neuroscience 0270-6474/00/2041358-07$05.00/0
This article has been cited by other articles:
A. Berna-Erro, A. Braun, R. Kraft, C. Kleinschnitz, M. K. Schuhmann, D. Stegner, T. Wultsch, J. Eilers, S. G. Meuth, G. Stoll, et al.
STIM2 Regulates Capacitive Ca2+ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death
Sci. Signal., October 20, 2009; 2(93): ra67 - ra67.
[Abstract] [Full Text] [PDF]
R. Polavarapu, J. An, C. Zhang, and M. Yepes
Regulated Intramembrane Proteolysis of the Low-Density Lipoprotein Receptor-Related Protein Mediates Ischemic Cell Death
Am. J. Pathol., May 1, 2008; 172(5): 1355 - 1362.
[Abstract] [Full Text] [PDF]
V. Dror, T. B. Kalynyak, Y. Bychkivska, M. H. Z. Frey, M. Tee, K. D. Jeffrey, V. Nguyen, D. S. Luciani, and J. D. Johnson
Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1{beta} via Presenilin in Pancreatic {beta}-Cells
J. Biol. Chem., April 11, 2008; 283(15): 9909 - 9916.
[Abstract] [Full Text] [PDF]
L. Baki, R. L. Neve, Z. Shao, J. Shioi, A. Georgakopoulos, and N. K Robakis
Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling
J. Neurosci., January 9, 2008; 28(2): 483 - 490.
[Abstract] [Full Text] [PDF]
Y. Zhang, G. G. Rodney, and M. F. Schneider
Effects of Azumolene on Ca2+ Sparks in Skeletal Muscle Fibers
J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 94 - 102.
[Abstract] [Full Text] [PDF]
H.-Q. Wang, Y. Nakaya, Z. Du, T. Yamane, M. Shirane, T. Kudo, M. Takeda, K. Takebayashi, Y. Noda, K. I. Nakayama, et al.
Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2
Hum. Mol. Genet., July 1, 2005; 14(13): 1889 - 1902.
[Abstract] [Full Text] [PDF]
A. Verkhratsky
Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons
Physiol Rev, January 1, 2005; 85(1): 201 - 279.
[Abstract] [Full Text] [PDF]
R. A. Christensen, A. Shtifman, P. D. Allen, J. R. Lopez, and H. W. Querfurth
Calcium Dyshomeostasis in {beta}-Amyloid and Tau-bearing Skeletal Myotubes
J. Biol. Chem., December 17, 2004; 279(51): 53524 - 53532.
[Abstract] [Full Text] [PDF]
Z. Xie, D. M. Romano, D. M. Kovacs, and R. E. Tanzi
Effects of RNA Interference-mediated Silencing of {gamma}-Secretase Complex Components on Cell Sensitivity to Caspase-3 Activation
J. Biol. Chem., August 13, 2004; 279(33): 34130 - 34137.
[Abstract] [Full Text] [PDF]
X. Xu, Y.-c. Shi, W. Gao, G. Mao, G. Zhao, S. Agrawal, G. M. Chisolm, D. Sui, and M.-Z. Cui
The Novel Presenilin-1-associated Protein Is a Proapoptotic Mitochondrial Protein
J. Biol. Chem., December 6, 2002; 277(50): 48913 - 48922.
[Abstract] [Full Text] [PDF]
T. Fath, J. Eidenmuller, and R. Brandt
Tau-Mediated Cytotoxicity in a Pseudohyperphosphorylation Model of Alzheimer's Disease
J. Neurosci., November 15, 2002; 22(22): 9733 - 9741.
[Abstract] [Full Text] [PDF]
T. Mengesdorf, P. H. Jensen, G. Mies, C. Aufenberg, and W. Paschen
Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?
PNAS, November 12, 2002; 99(23): 15042 - 15047.
[Abstract] [Full Text] [PDF]
N. G. Bazan and W. J. Lukiw
Cyclooxygenase-2 and Presenilin-1 Gene Expression Induced by Interleukin-1beta and Amyloid beta 42 Peptide Is Potentiated by Hypoxia in Primary Human Neural Cells
J. Biol. Chem., August 9, 2002; 277(33): 30359 - 30367.
[Abstract] [Full Text] [PDF]
J. Kipnis, E. Yoles, H. Schori, E. Hauben, I. Shaked, and M. Schwartz
Neuronal Survival after CNS Insult Is Determined by a Genetically Encoded Autoimmune Response
J. Neurosci., July 1, 2001; 21(13): 4564 - 4571.
[Abstract] [Full Text] [PDF]
S. M. Fitzjohn, R. A. Morton, F. Kuenzi, T. W. Rosahl, M. Shearman, H. Lewis, D. Smith, D. S. Reynolds, C. H. Davies, G. L. Collingridge, et al.
Age-Related Impairment of Synaptic Transmission But Normal Long-Term Potentiation in Transgenic Mice that Overexpress the Human APP695SWE Mutant Form of Amyloid Precursor Protein
J. Neurosci., July 1, 2001; 21(13): 4691 - 4698.
[Abstract] [Full Text] [PDF]
K. Takekoshi, K. Ishii, Y. Kawakami, K. Isobe, T. Nanmoku, and T. Nakai
Ca2+ Mobilization, Tyrosine Hydroxylase Activity, and Signaling Mechanisms in Cultured Porcine Adrenal Medullary Chromaffin Cells: Effects of Leptin
Endocrinology, January 1, 2001; 142(1): 290 - 298.
[Abstract] [Full Text] [PDF]
M. Grilli, E. Diodato, G. Lozza, R. Brusa, M. Casarini, D. Uberti, R. Rozmahel, D. Westaway, P. St George-Hyslop, M. Memo, et al.
Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically
PNAS, November 7, 2000; 97(23): 12822 - 12827.
[Abstract] [Full Text] [PDF]
C. Caspersen, P. S. Pedersen, and M. Treiman
The Sarco/Endoplasmic Reticulum Calcium-ATPase 2b Is an Endoplasmic Reticulum Stress-inducible Protein
J. Biol. Chem., July 14, 2000; 275(29): 22363 - 22372.
[Abstract] [Full Text] [PDF]
F. Zhao, P. Li, S. R. W. Chen, C. F. Louis, and B. R. Fruen
Dantrolene Inhibition of Ryanodine Receptor Ca2+ Release Channels. MOLECULAR MECHANISM AND ISOFORM SELECTIVITY
J. Biol. Chem., April 20, 2001; 276(17): 13810 - 13816.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|