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Physiological Reviews, Vol. 81, No. 2, April 2001, pp. 741-766
Copyright ©2001 by the American Physiological Society
Department of Neurology and Program in Neuroscience, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts
Selkoe, Dennis J.
Alzheimer's Disease: Genes, Proteins, and Therapy. Physiol. Rev. 81: 741-766, 2001.
Rapid progress in
deciphering the biological mechanism of Alzheimer's disease (AD) has
arisen from the application of molecular and cell biology to this
complex disorder of the limbic and association cortices. In turn, new
insights into fundamental aspects of protein biology have resulted from
research on the disease. This beneficial interplay between basic and
applied cell biology is well illustrated by advances in understanding
the genotype-to-phenotype relationships of familial Alzheimer's
disease. All four genes definitively linked to inherited forms of the
disease to date have been shown to increase the production and/or
deposition of amyloid 
-protein in the brain. In particular, evidence
that the presenilin proteins, mutations in which cause the most
aggressive form of inherited AD, lead to altered intramembranous
cleavage of the -amyloid precursor protein by the protease called
-secretase has spurred progress toward novel therapeutics. The
finding that presenilin itself may be the long-sought
-secretase, coupled with the recent identification of -secretase,
has provided discrete biochemical targets for drug screening and
development. Alternate and novel strategies for inhibiting the early
mechanism of the disease are also emerging. The progress reviewed here,
coupled with better ability to diagnose the disease early, bode well
for the successful development of therapeutic and preventative drugs
for this major public health problem.
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 L. Calderon-Garciduenas, A. C. Solt, C. Henriquez-Roldan, R. Torres-Jardon, B. Nuse, L. Herritt, R. Villarreal-Calderon, N. Osnaya, I. Stone, R. Garcia, et al. Long-term Air Pollution Exposure Is Associated with Neuroinflammation, an Altered Innate Immune Response, Disruption of the Blood-Brain Barrier, Ultrafine Particulate Deposition, and Accumulation of Amyloid {beta}-42 and {alpha}-Synuclein in Children and Young Adults Toxicol Pathol, February 1, 2008; 36(2): 289 - 310. [Abstract] [Full Text] [PDF]
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A. Ganguly, R.M. R. Feldman, and M. Guo ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila Hum. Mol. Genet., January 15, 2008; 17(2): 293 - 302. [Abstract] [Full Text] [PDF]
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S. Yagishita, M. Morishima-Kawashima, S. Ishiura, and Y. Ihara A 46 Is Processed to A 40 and A 43, but Not to A 42, in the Low Density Membrane Domains J. Biol. Chem., January 11, 2008; 283(2): 733 - 738. [Abstract] [Full Text] [PDF]
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S. Tagami, M. Okochi, K. Yanagida, A. Ikuta, A. Fukumori, N. Matsumoto, Y. Ishizuka-Katsura, T. Nakayama, N. Itoh, J. Jiang, et al. Regulation of Notch Signaling by Dynamic Changes in the Precision of S3 Cleavage of Notch-1 Mol. Cell. Biol., January 1, 2008; 28(1): 165 - 176. [Abstract] [Full Text] [PDF]
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L. G. Iben, R. E. Olson, L. A. Balanda, S. Jayachandra, B. J. Robertson, V. Hay, J. Corradi, C. V. C. Prasad, R. Zaczek, C. F. Albright, et al. Signal Peptide Peptidase and {gamma}-Secretase Share Equivalent Inhibitor Binding Pharmacology J. Biol. Chem., December 21, 2007; 282(51): 36829 - 36836. [Abstract] [Full Text] [PDF]
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Z. Ren, D. Schenk, G. S. Basi, and I. P. Shapiro Amyloid -Protein Precursor Juxtamembrane Domain Regulates Specificity of {gamma}-Secretase-dependent Cleavages J. Biol. Chem., November 30, 2007; 282(48): 35350 - 35360. [Abstract] [Full Text] [PDF]
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D. Goldblum, A. Kipfer-Kauer, G.-M. Sarra, S. Wolf, and B. E. Frueh Distribution of Amyloid Precursor Protein and Amyloid-{beta} Immunoreactivity in DBA/2J Glaucomatous Mouse Retinas Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 5085 - 5090. [Abstract] [Full Text] [PDF]
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M. E. Goldstein, Y. Cao, T. Fiedler, J. Toyn, L. Iben, D. M. Barten, M. Pierdomenico, J. Corsa, C. V. C. Prasad, R. E. Olson, et al. Ex Vivo Occupancy of {gamma}-Secretase Inhibitors Correlates with Brain beta-Amyloid Peptide Reduction in Tg2576 Mice J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 102 - 108. [Abstract] [Full Text] [PDF]
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 V. Lamarca, A. Sanz-Clemente, R. Perez-Pe, M. J. Martinez-Lorenzo, N. Halaihel, P. Muniesa, and J. A. Carrodeguas Two isoforms of PSAP/MTCH1 share two proapoptotic domains and multiple internal signals for import into the mitochondrial outer membrane Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1347 - C1361. [Abstract] [Full Text] [PDF]
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Z. Muresan and V. Muresan The Amyloid-beta Precursor Protein Is Phosphorylated via Distinct Pathways during Differentiation, Mitosis, Stress, and Degeneration Mol. Biol. Cell, October 1, 2007; 18(10): 3835 - 3844. [Abstract] [Full Text] [PDF]
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H. J. Huttunen, S. Y. Guenette, C. Peach, C. Greco, W. Xia, D. Y. Kim, C. Barren, R. E. Tanzi, and D. M. Kovacs HtrA2 Regulates beta-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation J. Biol. Chem., September 21, 2007; 282(38): 28285 - 28295. [Abstract] [Full Text] [PDF]
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L. McConlogue, M. Buttini, J. P. Anderson, E. F. Brigham, K. S. Chen, S. B. Freedman, D. Games, K. Johnson-Wood, M. Lee, M. Zeller, et al. Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice J. Biol. Chem., September 7, 2007; 282(36): 26326 - 26334. [Abstract] [Full Text] [PDF]
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 Z. Zhang, H. Chen, and L. Lai Identification of amyloid fibril-forming segments based on structure and residue-based statistical potential Bioinformatics, September 1, 2007; 23(17): 2218 - 2225. [Abstract] [Full Text] [PDF]
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Y. S. Eisele, M. Baumann, B. Klebl, C. Nordhammer, M. Jucker, and E. Kilger Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-beta degrading Enzyme Neprilysin Mol. Biol. Cell, September 1, 2007; 18(9): 3591 - 3600. [Abstract] [Full Text] [PDF]
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Y. I. Yin, B. Bassit, L. Zhu, X. Yang, C. Wang, and Y.-M. Li {gamma}-Secretase Substrate Concentration Modulates the Abeta42/Abeta40 Ratio: IMPLICATIONS FOR ALZHEIMER DISEASE J. Biol. Chem., August 10, 2007; 282(32): 23639 - 23644. [Abstract] [Full Text] [PDF]
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 H. Yamamoto, K. Schoonjans, and J. Auwerx Sirtuin Functions in Health and Disease Mol. Endocrinol., August 1, 2007; 21(8): 1745 - 1755. [Abstract] [Full Text] [PDF]
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Y. Lu, Y. Lv, Y. Ye, Y. Wang, Y. Hong, M. E. Fortini, Y. Zhong, and Z. Xie A role for presenilin in post-stress regulation: effects of presenilin mutations on Ca2+ currents in Drosophila FASEB J, August 1, 2007; 21(10): 2368 - 2378. [Abstract] [Full Text] [PDF]
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 A. Gomez-Brouchet, D. Pchejetski, L. Brizuela, V. Garcia, M.-F. Altie, M.-L. Maddelein, M.-B. Delisle, and O. Cuvillier Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-beta Peptide Mol. Pharmacol., August 1, 2007; 72(2): 341 - 349. [Abstract] [Full Text] [PDF]
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E. T. Parkin, N. T. Watt, I. Hussain, E. A. Eckman, C. B. Eckman, J. C. Manson, H. N. Baybutt, A. J. Turner, and N. M. Hooper Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein PNAS, June 26, 2007; 104(26): 11062 - 11067. [Abstract] [Full Text] [PDF]
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G. G. Farias, A. S. Valles, M. Colombres, J. A. Godoy, E. M. Toledo, R. J. Lukas, F. J. Barrantes, and N. C. Inestrosa Wnt-7a Induces Presynaptic Colocalization of {alpha}7-Nicotinic Acetylcholine Receptors and Adenomatous Polyposis Coli in Hippocampal Neurons J. Neurosci., May 16, 2007; 27(20): 5313 - 5325. [Abstract] [Full Text] [PDF]
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K. Prager, L. Wang-Eckhardt, R. Fluhrer, R. Killick, E. Barth, H. Hampel, C. Haass, and J. Walter A Structural Switch of Presenilin 1 by Glycogen Synthase Kinase 3beta-mediated Phosphorylation Regulates the Interaction with beta-Catenin and Its Nuclear Signaling J. Biol. Chem., May 11, 2007; 282(19): 14083 - 14093. [Abstract] [Full Text] [PDF]
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A. Caccamo, S. Oddo, L. X. Tran, and F. M. LaFerla Lithium Reduces Tau Phosphorylation but Not A{beta} or Working Memory Deficits in a Transgenic Model with Both Plaques and Tangles Am. J. Pathol., May 1, 2007; 170(5): 1669 - 1678. [Abstract] [Full Text] [PDF]
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 C.-Y. Lin, T. Gurlo, R. Kayed, A. E. Butler, L. Haataja, C. G. Glabe, and P. C. Butler Toxic Human Islet Amyloid Polypeptide (h-IAPP) Oligomers Are Intracellular, and Vaccination to Induce Anti-Toxic Oligomer Antibodies Does Not Prevent h-IAPP-Induced {beta}-Cell Apoptosis in h-IAPP Transgenic Mice Diabetes, May 1, 2007; 56(5): 1324 - 1332. [Abstract] [Full Text] [PDF]
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N. Moretto, A. Bolchi, C. Rivetti, B. P. Imbimbo, G. Villetti, V. Pietrini, L. Polonelli, S. Del Signore, K. M. Smith, R. J. Ferrante, et al. Conformation-sensitive Antibodies against Alzheimer Amyloid-beta by Immunization with a Thioredoxin-constrained B-cell Epitope Peptide J. Biol. Chem., April 13, 2007; 282(15): 11436 - 11445. [Abstract] [Full Text] [PDF]
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X. He, K. Cooley, C. H. Y. Chung, N. Dashti, and J. Tang Apolipoprotein Receptor 2 and X11{alpha}/{beta} Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-{beta} Precursor Protein and {beta}-Secretase, Leading to Amyloid-{beta} Production J. Neurosci., April 11, 2007; 27(15): 4052 - 4060. [Abstract] [Full Text] [PDF]
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T. Kanekiyo, T. Ban, K. Aritake, Z.-L. Huang, W.-M. Qu, I. Okazaki, I. Mohri, S. Murayama, K. Ozono, M. Taniike, et al. Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloid beta-chaperone in human cerebrospinal fluid PNAS, April 10, 2007; 104(15): 6412 - 6417. [Abstract] [Full Text] [PDF]
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A. Majumdar, D. Cruz, N. Asamoah, A. Buxbaum, I. Sohar, P. Lobel, and F. R. Maxfield Activation of Microglia Acidifies Lysosomes and Leads to Degradation of Alzheimer Amyloid Fibrils Mol. Biol. Cell, April 1, 2007; 18(4): 1490 - 1496. [Abstract] [Full Text] [PDF]
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S.-R. Hwang, C. Garza, C. Mosier, T. Toneff, E. Wunderlich, P. Goldsmith, and V. Hook Cathepsin L Expression Is Directed to Secretory Vesicles for Enkephalin Neuropeptide Biosynthesis and Secretion J. Biol. Chem., March 30, 2007; 282(13): 9556 - 9563. [Abstract] [Full Text] [PDF]
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E. Planel, K. E. G. Richter, C. E. Nolan, J. E. Finley, L. Liu, Y. Wen, P. Krishnamurthy, M. Herman, L. Wang, J. B. Schachter, et al. Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia J. Neurosci., March 21, 2007; 27(12): 3090 - 3097. [Abstract] [Full Text] [PDF]
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G. M. Shankar, B. L. Bloodgood, M. Townsend, D. M. Walsh, D. J. Selkoe, and B. L. Sabatini Natural Oligomers of the Alzheimer Amyloid-{beta} Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway J. Neurosci., March 14, 2007; 27(11): 2866 - 2875. [Abstract] [Full Text] [PDF]
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J. Boddaert, K. Kinugawa, J.-C. Lambert, F. Boukhtouche, J. Zoll, R. Merval, O. Blanc-Brude, D. Mann, C. Berr, J. Vilar, et al. Evidence of a Role for Lactadherin in Alzheimer's Disease Am. J. Pathol., March 1, 2007; 170(3): 921 - 929. [Abstract] [Full Text] [PDF]
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W. V. Nikolic, Y. Bai, D. Obregon, H. Hou, T. Mori, J. Zeng, J. Ehrhart, R. D. Shytle, B. Giunta, D. Morgan, et al. Transcutaneous beta-amyloid immunization reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage PNAS, February 13, 2007; 104(7): 2507 - 2512. [Abstract] [Full Text] [PDF]
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