Alzheimer’s disease (AD) is a neurodegenerative disease characterized by senile plaques and neurofibrillary tangles. Senile plaques are deposits of amyloid ß-peptide (Aß) produced by the cleavage of a transmembrane protein termed Amyloid Precursor Protein (APP). The amyloidogenic cleavage of APP is performed by γ-secretase complex and ß-site APP cleaving enzyme 1 (BACE1), a key enzyme in AD that can be activated by different noxious stimuli. Interestingly, some viruses could activate double-stranded RNA-activated protein kinase (PKR), which phosphorylates Eukaryotic Initiation Factor 2 alpha (eIF2α). This phosphorylation stops global translation to avoid any synthesis of viral infective proteins, but paradoxically up-regulates BACE1 translation. One of the viral mechanisms to circumvent eIF2α phosphorylation is the recruitment of protein phosphatase 1 (PP1), to fully dephosphorylate eIF2α and allow viral protein synthesis. Due to the functional relationship between BACE1, PKR, PP1 and AD we have performed a large (1122 cases and 1191 control individuals) case-control genetic analysis using two biallelic polymorphisms rs2254958 and rs7480390, located within the genes coding for PKR and the catalytic unit A of PP1, respectively. Although a trend to association of the rs2254958 TT genotype with AD risk was found, our results show that neither rs7480390 nor rs2254958 are associated with AD susceptibility.
KeywordsAlzheimer’s DiseaseBACE1PKRPP1eIF2α
J. Lewis, D. W. Dickson, W. L. Lin, L. Chisholm, A. Corral, G. Jones, S. H. Yen, N. Sahara, L. Skipper, D. Yager, C. Eckman, J. Hardy, M. Hutton, and E. McGowan, “Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP,” Science, Vol. 293, No. 5534, 2001, pp. 1487-1491. doi:10.1126/science.1058189
G. G. Glenner and C. W. Wong, “Alzheimer’s Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein,” Biochemical and Biophysical Research Communications, Vol. 120, No. 3, 1984, pp. 885-890.
C. L. Masters, G. Simms, N. A. Weinman, G. Multhaup, B. L. McDonald and K. Beyreuther, “Amyloid Plaque Core Protein in Alzheimer Disease and Down Syndrome,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 82, No. 12, 1985, pp. 4245-4249.
D. J. Selkoe, C. R. Abraham, M. B. Podlisny and L. K. Duffy, “Isolation of Low-Molecular-Weight Proteins from Amyloid Plaque Fibers in Alzheimer’s Disease,” Journal of Neurochemistry, Vol. 46, No. 6, 1986, pp. 1820-1834.
S. B. De, P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, F. K. Von and L. F. Van, “Deficien- cy of Presenilin-1 Inhibits the Normal Cleavage of Amyloid Precursor Protein,” Nature, Vol. 391, No. 6665, 1998, pp. 387-390. doi:10.1038/34910.
R. Vassar, B. D. Bennett, S. Babu-Khan, S. Kahn, E. A. Mendiaz, P. Denis, D. B. Teplow, S. Ross, P. Amarante, R. Loeloff, Y. Luo, S. Fisher, J. Fuller, S. Edenson, J. Lile, M. A. Jarosinski, A. L. Biere, E. Curran, T. Burgess, J. C. Louis, F. Collins, J. Treanor, G. Rogers and M. Citron, “Beta-Secretase Cleavage of Alzheimer’s Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE,” Science, Vol. 286, No. 5440, 1999, pp. 735-741. doi:10.1126/science.286.5440.735.
D. Del Toro, M. Coma, I. Uribesalgo, F. X. Guix and F. J. Munoz, “The Amyloid Betaprotein Precursor and Alz- Heimer’s Disease. Therapeutic Approaches,” Current Medicinal Chemistry - Central Nervous System Agents, Vol. 5, 2005, pp. 271-281.
D. Scheuner, C. Eckman, M. Jensen, X. Song, M. Citron, N. Suzuki, T. D. Bird, J. Hardy, M. Hutton, W. Kukull, E. Larson, E. Levy-Lahad, M. Viitanen, E. Peskind, P. Poorkaj, G. Schellenberg, R. Tanzi, W. Wasco, L. Lann- felt, D. Selkoe and S. Younkin, “Secreted Amyloid Beta- Protein Similar to That in the Senile Plaques of Alzheimer’s Disease Is Increased in Vivo by The Presenilin 1 and 2 and APP Mutations Linked to Familial Alzheimer’s Disease,” Nature Medicine, Vol. 2, No. 8, 1996, pp. 864- 870.
M. Bentahir, O. Nyabi, J. Verhamme, A. Tolia, K. Horre, J. Wiltfang, H. Esselmann and S. B. De, “Presenilin cli- nical Mutations Can Affect Gamma-Secretase Activity by Different Mechanisms,” Journal of Neurochemistry, Vol. 96, No. 3, 2006, pp. 732-742. doi:10.1111/j.1471-4159.2005.03578.x
T. Wakabayashi and S. B. De, “Presenilins: Members of the Gamma-Secretase Quartets, but Part-Time Soloists too,” Physiology (Bethesda), Vol. 23, 2008, pp. 194-204. doi:10.?1152/physiol.00009.2008
K. S. Vetrivel, Y. W. Zhang, H. Xu and G. Thinakaran, “Pathological and Physiological Functions of Presenilins,” Molecular Neurodegeneration., Vol. 1, 2006, p. 4
J. C. Lambert and P. Amouyel, “Genetic Heterogeneity of Alzheimer’s Disease: Complexity and Advances,” Psychoneuroendocrinology, Vol. 32, Suppl 1, 2007, pp. S62- S70.
L. Bertram and R. E. Tanzi, “Alzheimer’s Disease: One Disorder, Too Many Genes?” Human Molecular Genetics, Vol. 13, Spec No. 1, 2004, pp. R135-R141.
D. S. Borgaonkar, L. C. Schmidt, S. E. Martin, M. D. Kanzer, L. Edelsohn, J. Growdon and L. A. Farrer, “Linkage of Late-Onset Alzheimer’s Disease with Apolipo-Protein E Type 4 on Chromosome 19,” Lancet, Vol. 342, No. 8871, 1993, pp. 625
R. F. Itzhaki and M. A. Wozniak, “Herpes Simplex Virus Type 1 in Alzheimer’s Disease: The Enemy within,” Journal of Alzheimer’s Disease, Vol. 13, No. 4, 2008, pp. 393-405.
M. A. Wozniak and R. F. Itzhaki, “Antiviral Agents in Alzheimer’s Disease: Hope for the Future?” Therapeutic Advances in Neurological Disorders, Vol. 3, No. 3, 2010, pp. 141-152.
Gerard ILL-Raga, Ernest Palomer, Matthew Wozniak, Eva Ramos-Fernández, MònicaBosch-Morato, Marta Ta- jes, Francesc Guix, José Galán, Jordi Clarimón, Carmen Antúnez, Luis M.Real, Cesar Fandos, Mercé Boada, Ruth Itzhaki and F. J. Munoz, “Activation of PKR Causes Amyloid ?-Peptide Accumulation via De-Repression of BACE1 Expression,” PlosOne, Vol. 6, No. 6, 2011, pp. e21456. doi:10.1371/journal.pone.0021456.g001
R. C. Chang, A. K. Wong, H. K. Ng and J. Hugon, “Phosphorylation of Eukaryotic Initiation Factor-2alpha (eIF2alpha) is Associated with Neuronal Degeneration in Alzheimer’s Disease,” Neuroreport, Vol. 13, No. 18, 2002, pp. 2429-2432.
A. L. Peel and D. E. Bredesen, “Activation of the cell stress kinase PKR in Alzheimer’s Disease and Human Amyloid Precursor Protein Transgenic Mice,” Neurobiology of Disease, Vol. 14, No. 1, 2003, pp. 52-62.
M. J. Bullido, A. Martinez-Garcia, R. Tenorio, I. Sastre, D. G. Munoz, A. Frank and F. Valdivieso, “Double Stranded RNA Activated EIF2 Alpha Kinase (EIF2AK2; PKR) is Associated with Alzheimer’s Disease,” Neurobiology of Aging, Vol. 29, No. 8, 2008, pp. 1160-1166. doi:10.1016/j.neurobiolaging.2007.02.023
B. R. Williams, “PKR; A Sentinel Kinase for Cellular Stress,” Oncogene, Vol. 18, No. 45, 1999, pp. 6112-6120.
T. O’Connor, K. R. Sadleir, E. Maus, R. A. Velliquette, J. Zhao, S. L. Cole, W. A. Eimer, B. Hitt, L. A. Bembinster, S. Lammich, S. F. Lichtenthaler, S. S. Hebert, S. B. De, C. Haass, D. A. Bennett and R. Vassar, “Phosphorylation of the Translation Initiation Factor eIF2alpha Increases BACE1 Levels and Promotes Amyloidogenesis,” Neuron, Vol. 60, No. 6, 26-12-2008, pp. 988-1009. doi:10.1016/j.neuron.2008.10.047.
B. He, M. Gross and B. Roizman, “The Gamma(1)34.5 Protein of Herpes Simplex Virus 1 Complexes with Protein Phosphatase 1alpha to Dephosphorylate the Alpha Subunit of the Eukaryotic Translation Initiation Factor 2 and Preclude the Shutoff of Protein Synthesis by Double-Stranded RNA-Activated Protein Kinase,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 3, 1997, pp. 843-848.
G. McKhann, D. Drachman, M. Folstein, R. Katzman, D. Price and E. M. Stadlan, “Clinical Diagnosis of Alz- heimer’s Disease: Report of the NINCDS-ADRDA Work Group under the Auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease,” Neurology, Vol. 34, No. 7, 1984, pp. 939-944.
R. Ramirez-Lorca, M. Boada, M. E. Saez, I. Hernandez, A. Mauleon, M. Rosende-Roca, P. Martinez-Lage, M. Gutierrez, L. M. Real, J. Lopez-Arrieta, J. Gayan, C. An- tunez, A. Gonzalez-Perez, L. Tarraga and A. Ruiz, “GAB2 Gene Does Not Modify the Risk of Alzheimer’s Disease in Spanish APOE 4 Carriers,” Journal of Nutrition Health and Aging, Vol. 13, No. 3, 2009, pp. 214-219.
A. varez-Arcaya, O. Combarros, J. Llorca, M. Sanchez- Guerra, J. Berciano and J. L. Fernandez-Luna, “The - 491 TT Apolipoprotein E Promoter Polymorphism Is Associated with Reduced Risk for Sporadic Alzheimer’s Disease,” Neuroscience Letters, Vol. 304, No. 3, 2001, pp. 204-208. doi:10.1016/S0304-3940(01)01790-6
J. C. Lambert, F. Pasquier, D. Cottel, B. Frigard, P. Amouyel and M. C. Chartier-Harlin, “A New Polymer- Phism in the APOE Promoter Associated with Risk of Developing Alzheimer’s Disease,” Human Molecular Genetics, Vol. 7, No. 3, 1998, pp. 533-540. doi:10.1093/hmg/7.3.533
E. H. Corder, A. M. Saunders, W. J. Strittmatter, D. E. Schmechel, P. C. Gaskell, G. W. Small, A. D. Roses, J. L. Haines and M. A. Pericak-Vance, “Gene Dose of Apoli- Poprotein E Type 4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families,” Science, Vol. 261, No. 5123, 1993, pp. 921-923.
J. Clarimon, F. J. Munoz, M. Boada, L. Tarraga, J. Sun- yer, J. Bertranpetit and D. Comas, “Possible Increased Risk for Alzheimer’s Disease Associated with Neprilysin Gene,” Journal of Neural Transmission, Vol. 110, No. 6, 2003, pp. 651-657.
G. A. Jamieson, N. J. Maitland, G. K. Wilcock, J. Craske and R. F. Itzhaki, “Latent Herpes Simplex Virus Type 1 in Normal and Alzheimer’s Disease Brains,” Journal of Medical Virology, Vol. 33, No. 4, 1991, pp. 224-227.
M. A. Wozniak, S. J. Shipley, M. Combrinck, G. K. Wil- cock and R. F. Itzhaki, “Productive Herpes Simplex Virus in Brain of Elderly Normal Subjects and Alzheimer’s Dis- Ease Patients,” Journal of Medical Virology, Vol. 75, No. 2, 2005, pp. 300-306.
M. J. Ball, “Limbic Predilection in Alzheimer Dementia: Is Reactivated Herpesvirus Involved?” Canadian Journal Neurological Sciences, Vol. 9, No. 3, 1982, pp. 303-306.
R. F. Itzhaki, W. R. Lin, G. K. Wilcock and B. Faragher, “HSV-1 and Risk of Alzheimer’s Disease,” Lancet, Vol. 352, No. 9123, 18-7-1998, p. 238
S. R. Nallagatla, R. Toroney and P. C. Bevilacqua, “Re- gulation of Innate Immunity through RNA Structure and the Protein Kinase PKR,” Current Opinion in Structural Biology, Vol. 21, No. 1, 2011, pp. 119-127. doi10.1016/j.sbi.2010.11.003
G. Li, C. Scull, L. Ozcan and I. Tabas, “NADPH Oxidase Links Endoplasmic Reticulum Stress, Oxidative Stress, and PKR Activation to Induce Apoptosis,” Journal of Cell Biology, Vol. 191, No. 6, 2010, pp. 1113-1125. doi:10.1083/jcb.201006121.