The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of alzheimer disease

Journal of Biological Chemistry

Volumn 290, Issue 9, 2015, Pages 5311-5327

  Prasad, Hari ^a   Rao, Rajini ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL CULTURE; CELLS; CYTOLOGY; ENZYMES; GLYCOPROTEINS; IONOPHORES; NEURODEGENERATIVE DISEASES; PATIENT TREATMENT; PROTEINS; PROTONS; SODIUM;

AMYLOID PRECURSOR PROTEINS; CELL CULTURE MODELS; EARLY INTERVENTION; ENDOSOMAL COMPARTMENTS; NEUROBLASTOMA CELLS; PATHWAY FOR PROTONS; RECYCLING ENDOSOMES; TRANS-GOLGI NETWORK;

DISEASE CONTROL;

AMYLOID PRECURSOR PROTEIN; BETA SECRETASE; SODIUM PROTON EXCHANGE PROTEIN; AMYLOID BETA PROTEIN; GREEN FLUORESCENT PROTEIN; MONENSIN; PROTON IONOPHORE; SLC9A6 PROTEIN, HUMAN;

ALZHEIMER DISEASE; APP GENE; ARTICLE; BACE1 GENE; BRAIN CORTEX; BRAIN REGION; CELL MIGRATION; CELL PH; CEREBELLUM; ENDOSOME; GENE; GOLGI COMPLEX; GRAY MATTER; HIPPOCAMPUS; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNE RESPONSE; INNATE IMMUNITY; NEUROBLASTOMA CELL; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PROCESSING; PSEN2 GENE; PURKINJE CELL; AGED; BIOLOGICAL MODEL; BRAIN; CHEMISTRY; CONFOCAL MICROSCOPY; DRUG EFFECTS; GENE EXPRESSION; GENETICS; HEK293 CELL LINE; MALE; METABOLISM; PATHOLOGY; PROTEIN TRANSPORT; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA INTERFERENCE; TRANS GOLGI NETWORK; TUMOR CELL LINE; VERY ELDERLY; WESTERN BLOTTING;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID BETA-PROTEIN PRECURSOR; BLOTTING, WESTERN; BRAIN; CELL LINE, TUMOR; ENDOSOMES; GENE EXPRESSION; GREEN FLUORESCENT PROTEINS; HEK293 CELLS; HUMANS; MALE; MICROSCOPY, CONFOCAL; MODELS, BIOLOGICAL; MONENSIN; PROTEIN TRANSPORT; PROTON IONOPHORES; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA INTERFERENCE; SODIUM-HYDROGEN ANTIPORTER; TRANS-GOLGI NETWORK;

EID: 84923767161     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.602219     Document Type: Article

References (75)

1. + exchangers link to autism and neurological disease. Front. Cell Neurosci. 8, 172
2. + exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am. J. Physiol. Cell Physiol. 282, C1031-C1041
3. Brett, C. L., Tukaye, D. N., Mukherjee, S., and Rao, R. (2005) The yeast endosomal Na+K+/H+ exchanger Nhx1 regulates cellular pH to control vesicle trafficking. Mol. Biol. Cell 16, 1396-1405
4. + exchanger in a late endosomal compartment of yeast: implications for vacuole biogenesis. J. Biol. Chem. 273, 21054-21060
5. Bowers, K., Levi, B. P., Patel, F. I., and Stevens, T. H. (2000) The sodium/ proton exchanger Nhx1p is required for endosomal protein trafficking in the yeast Saccharomyces cerevisiae. Mol. Biol. Cell 11, 4277-4294
6. Brett, C. L., Kallay, L., Hua, Z., Green, R., Chyou, A., Zhang, Y., Graham, T. R., Donowitz, M., and Rao, R. (2011) Genome-wide analysis reveals the vacuolar pH-stat of Saccharomyces cerevisiae. PLoS One 6, e17619
7. Wolfe, D. M., Lee, J. H., Kumar, A., Lee, S., Orenstein, S. J., and Nixon, R. A. (2013) Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 37, 1949-1961
8. Cataldo, A. M., Mathews, P. M., Boiteau, A. B., Hassinger, L. C., Peterhoff, C. M., Jiang, Y., Mullaney, K., Neve, R. L., Gruenberg, J., and Nixon, R. A. (2008) Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am. J. Pathol. 173, 370-384
9. Karch, C. M., and Goate, A. M. (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43-51
10. Das, U., Scott, D. A., Ganguly, A., Koo, E. H., Tang, Y., and Roy, S. (2013) Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 79, 447-460
11. Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M. A., Biere, A. L., Curran, E., Burgess, T., Louis, J. C., Collins, F., Treanor, J., Rogers, G., and Citron, M. (1999) β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735-741
12. Cai, H., Wang, Y., McCarthy, D., Wen, H., Borchelt, D. R., Price, D. L., and Wong, P. C. (2001) BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 4, 233-234
13. Olubiyi, O. O., and Strodel, B. (2012) Structures of the amyloid β-peptides Aβ1-40 and Aβ1-42 as influenced by pH and a D-peptide. J. Phys. Chem. B 116, 3280-3291
14. Caglayan, S., Takagi-Niidome, S., Liao, F., Carlo, A. S., Schmidt, V., Burgert, T., Kitago, Y., Füchtbauer, E. M., Füchtbauer, A., Holtzman, D. M., Takagi, J., and Willnow, T. E. (2014) Lysosomal sorting of amy-loid-βby the SORLA receptor is impaired by a familial Alzheimer's disease mutation. Sci. Transl. Med. 6, 223ra20
15. Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., Greenman, C., Xue, Y., Tyler-Smith, C., Thompson, D., Gray, K., Andrews, J., Barthorpe, S., Buck, G., Cole, J., Dunmore, R., Jones, D., Maddison, M., Mironenko, T., Turner, R., Turrell, K., Varian, J., West, S., Widaa, S., Wray, P., Teague, J., Butler, A., Jenkinson, A., Jia, M., Richardson, D., Shepherd, R., Wooster, R., Tejada, M. I., Martinez, F., Carvill, G., Goliath, R., de Brouwer, A. P., van Bokhoven, H., Van Esch, H., Chelly, J., Raynaud, M., Ropers, H. H., Abidi, F. E., Srivastava, A. K., Cox, J., Luo, Y., Mallya, U., Moon, J., Parnau, J., Mohammed, S., Tolmie, J. L., Shoubridge, C., Corbett, M., Gardner, A., Haan, E., Rujirabanjerd, S., Shaw, M., Vandeleur, L., Fullston, T., Easton, D. F., Boyle, J., Partington, M., Hackett, A., Field, M., Skinner, C., Stevenson, R. E., Bobrow, M., Turner, G., Schwartz, C. E., Gecz, J., Raymond, F. L., Futreal, P. A., and Stratton, M. R. (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat. Genet. 41, 535-543
16. Gilfillan, G. D., Selmer, K. K., Roxrud, I., Smith, R., Kyllerman, M., Eiklid, K., Kroken, M., Mattingsdal, M., Egeland, T., Stenmark, H., Sjøholm, H., Server, A., Samuelsson, L., Christianson, A., Tarpey, P., Whibley, A., Stratton, M. R., Futreal, P. A., Teague, J., Edkins, S., Gecz, J., Turner, G., Raymond, F. L., Schwartz, C., Stevenson, R. E., Undlien, D. E., and Strømme, P. (2008) SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am. J. Hum. Genet. 82, 1003-1010
17. Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., and Morrow, E. M. (2013) Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron 80, 97-112
18. Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M., Feldman, G., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R., and Sima, A. A. (2010) A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain 133, 1391-1402
19. Schwede, M., Garbett, K., Mirnics, K., Geschwind, D. H., and Morrow, E. M. (2014) Genes for endosomal NHE6 and NHE9 are misregulated in autism brains. Mol. Psychiatry 19, 277-279
20. Vos, S. J., Xiong, C., Visser, P. J., Jasielec, M. S., Hassenstab, J., Grant, E. A., Cairns, N. J., Morris, J. C., Holtzman, D. M., and Fagan, A. M. (2013) Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957-965
21. Wegiel, J., Frackowiak, J., Mazur-Kolecka, B., Schanen, N. C., Cook, E. H., Jr., Sigman, M., Brown, W. T., Kuchna, I., Wegiel, J., Nowicki, K., Imaki, H., Ma, S. Y., Chauhan, A., Chauhan, V., Miller, D. L., Mehta, P. D., Flory, M., Cohen, I. L., London, E., Reisberg, B., de Leon, M. J., and Wisniewski, T. (2012) Abnormal intracellular accumulation and extracellular Aβ deposition in idiopathic and Dup15q11.2-q13 autism spectrum disorders. PLoS One 7, e35414
22. Westmark, C. J., and Malter, J. S. (2007) FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol. 5, e52
23. Sokol, D. K., Chen, D., Farlow, M. R., Dunn, D. W., Maloney, B., Zimmer, J. A., and Lahiri, D. K. (2006) High levels of Alzheimer β-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. J. Child Neurol. 21, 444-449
24. Hauser, M. A., Li, Y. J., Xu, H., Noureddine, M. A., Shao, Y. S., Gullans, S. R., Scherzer, C. R., Jensen, R. V., McLaurin, A. C., Gibson, J. R., Scott, B. L., Jewett, R. M., Stenger, J. E., Schmechel, D. E., Hulette, C. M., and Vance, J. M. (2005) Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch. Neurol. 62, 917-921
25. Martinelli-Boneschi, F., Giacalone, G., Magnani, G., Biella, G., Coppi, E., Santangelo, R., Brambilla, P., Esposito, F., Lupoli, S., Clerici, F., Benussi, L., Ghidoni, R., Galimberti, D., Squitti, R., Confaloni, A., Bruno, G., Pichler, S., Mayhaus, M., Riemenschneider, M., Mariani, C., Comi, G., Scarpini, E., Binetti, G., Forloni, G., Franceschi, M., and Albani, D. (2013) Pharmacogenomics in Alzheimer's disease: a genome-wide association study of response to cholinesterase inhibitors. Neurobiol. Aging 10.1016/ j.neurobiolaging.2012.12.008
26. Meda, S. A., Narayanan, B., Liu, J., Perrone-Bizzozero, N. I., Stevens, M. C., Calhoun, V. D., Glahn, D. C., Shen, L., Risacher, S. L., Saykin, A. J., and Pearlson, G. D. (2012) A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer's disease in the ADNI cohort. Neuroimage 60, 1608-1621
27. Encinas, M., Iglesias, M., Liu, Y., Wang, H., Muhaisen, A., Ceña, V., Gallego, C., and Comella, J. X. (2000) Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J. Neurochem. 75, 991-1003
28. Kondapalli, K. C., Hack, A., Schushan, M., Landau, M., Ben-Tal, N., and Rao, R. (2013) Functional evaluation of autism-associated mutations in NHE9. Nat. Commun. 4, 2510
29. Kim, M. K., Min, D. J., Rabin, M., and Licht, J. D. (2011) Functional characterization of Wilms tumor-suppressorWTXand tumor-associated mutants. Oncogene 30, 832-842
30. Vetrivel, K. S., Meckler, X., Chen, Y., Nguyen, P. D., Seidah, N. G., Vassar, R., Wong, P. C., Fukata, M., Kounnas, M. Z., and Thinakaran, G. (2009) Alzheimer disease Abeta production in the absence of S-palmitoylationdependent targeting of BACE1 to lipid rafts. J. Biol. Chem. 284, 3793-3803
31. + exchanger NHE6 into dendritic spines of hippocampal pyramidal neurons during NMDA receptor-dependent long-term potentiation. J. Neurosci. 33, 595-610
32. Demars, M., Hu, Y. S., Gadadhar, A., and Lazarov, O. (2010) Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J. Neurosci. Res. 88, 2103-2117
33. Zhang, B., Gaiteri, C., Bodea, L. G., Wang, Z., McElwee, J., Podtelezhnikov, A. A., Zhang, C., Xie, T., Tran, L., Dobrin, R., Fluder, E., Clurman, B., Melquist, S., Narayanan, M., Suver, C., Shah, H., Mahajan, M., Gillis, T., Mysore, J., MacDonald, M. E., Lamb, J. R., Bennett, D. A., Molony, C., Stone, D. J., Gudnason, V., Myers, A. J., Schadt, E. E., Neumann, H., Zhu, J., and Emilsson, V. (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707-720
34. Kohn, K. W., Zeeberg, B. M., Reinhold, W. C., and Pommier, Y. (2014) Gene expression correlations in human cancer cell lines define molecular interaction networks for epithelial phenotype. PLoS One 9, e99269
35. Hardy, J., Bogdanovic, N., Winblad, B., Portelius, E., Andreasen, N., Cedazo-Minguez, A., and Zetterberg, H. (2014) Pathways to Alzheimer's disease. J. Intern. Med. 275, 296-303
36. DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A., Aronow, B. J., Bales, K. R., Paul, S. M., and Holtzman, D. M. (2004) ApoE and clusterin cooperatively suppress Aβ levels and deposition: evidence that ApoE regulates extracellular Aβ metabolism in vivo. Neuron 41, 193-202
37. Malik, M., Simpson, J. F., Parikh, I., Wilfred, B. R., Fardo, D. W., Nelson, P. T., and Estus, S. (2013) CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing. J. Neurosci. 33, 13320-13325
38. Kanatsu, K., Morohashi, Y., Suzuki, M., Kuroda, H., Watanabe, T., Tomita, T., and Iwatsubo, T. (2014) DecreasedCALMexpression reduces Aβ2 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase. Nat. Commun. 5, 3386
39. König, G., Masters, C. L., and Beyreuther, K. (1990) Retinoic acid induced differentiated neuroblastoma cells show increased expression of the β A4 amyloid gene of Alzheimer's disease and an altered splicing pattern. FEBS Lett. 269, 305-310
40. Choy, R. W., Cheng, Z., and Schekman, R. (2012) Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid beta (Abeta) production in the trans-Golgi network. Proc. Natl. Acad. Sci. U.S.A. 109, E2077-E2082
41. Nyasae, L. K., Schell, M. J., and Hubbard, A. L. (2014) Copper directs ATP7B to the apical domain of hepatic cells via basolateral endosomes. Traffic 15, 1344-1365
42. Mollenhauer, H. H., Morré, D. J., and Rowe, L. D. (1990) Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochim. Biophys. Acta 1031, 225-246
43. + exchanger proteins. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L809-L817
44. +exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. Am. J. Physiol. Cell Physiol. 301, C1431-C1444
45. Itoh, N., Okochi, M., Tagami, S., Nishitomi, K., Nakayama, T., Yanagida, K., Fukumori, A., Jiang, J., Mori, K., Hosono, M., Kikuchi, J., Nakano, Y., Takinami, Y., Dohi, K., Nishigaki, A., Takemoto, H., Minagawa, K., Katoh, T., Willem, M., Haass, C., Morihara, T., Tanaka, T., Kudo, T., Hasegawa, H., Nishimura, M., Sakaguchi, G., Kato, A., and Takeda, M. (2009) Destruxin E decreases β-amyloid generation by reducing colocalization of β-amyloid-cleaving enzyme 1 and β-amyloid protein precursor. Neurodegener. Dis. 6, 230-239
46. Caporaso, G. L., Gandy, S. E., Buxbaum, J. D., and Greengard, P. (1992) Chloroquine inhibits intracellular degradation but not secretion of Alzheimer β/A4 amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 89, 2252-2256
47. Wolozin, B., Bacic, M., Merrill, M. J., Lesch, K. P., Chen, C., Lebovics, R. S., and Sunderland, T. (1992) Differential expression of carboxyl terminal derivatives of amyloid precursor protein among cell lines. J. Neurosci. Res. 33, 163-169
48. Lahiri, D. K. (1994) Effect of ionophores on the processing of the β-amyloid precursor protein in different cell lines. Cell. Mol. Neurobiol. 14, 297-313
49. Urmoneit, B., Turner, J., and Dyrks, T. (1998) Pulse-chase experiments revealed β-secretase cleavage from immature full-length amyloid precursor protein harboring the Swedish mutation: implications for distinct pathways. J. Mol. Neurosci. 11, 141-150
50. Blalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., and Landfield, P. W. (2004) Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc. Natl. Acad. Sci. U.S.A. 101, 2173-2178
51. Dunckley, T., Beach, T. G., Ramsey, K. E., Grover, A., Mastroeni, D., Walker, D. G., LaFleur, B. J., Coon, K. D., Brown, K. M., Caselli, R., Kukull, W., Higdon, R., McKeel, D., Morris, J. C., Hulette, C., Schmechel, D., Reiman, E. M., Rogers, J., and Stephan, D. A. (2006) Gene expression correlates of neurofibrillary tangles in Alzheimer's disease. Neurobiol. Aging 27, 1359-1371
52. Liang, W. S., Dunckley, T., Beach, T. G., Grover, A., Mastroeni, D., Walker, D. G., Caselli, R. J., Kukull, W. A., McKeel, D., Morris, J. C., Hulette, C., Schmechel, D., Alexander, G. E., Reiman, E. M., Rogers, J., and Stephan, D. A. (2007) Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiol. Genomics 28, 311-322
53. Nunez-Iglesias, J., Liu, C. C., Morgan, T. E., Finch, C. E., and Zhou, X. J. (2010) Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease cortex reveals altered miRNA regulation. PLoS One 5, e8898
54. O'Brien, R. J., and Wong, P. C. (2011) Amyloid precursor protein processing and Alzheimer's disease. Annu. Rev. Neurosci. 34, 185-204
55. Wang, Z., Yang, L., and Zheng, H. (2012) Role of APP and Aβ in synaptic physiology. Curr. Alzheimer Res. 9, 217-226
56. Frost, B., Götz, J., and Feany, M. B. (2015) Connecting the dots between tau dysfunction and neurodegeneration. Trends Cell Biol. 25, 46-53
57. Gómez Ravetti, M., Rosso, O. A., Berretta, R., and Moscato, P. (2010) Uncovering molecular biomarkers that correlate cognitive decline with the changes of hippocampus' gene expression profiles in Alzheimer's disease. PLoS One 5, e10153
58. Lee, C., Kang, H. J., von Ballmoos, C., Newstead, S., Uzdavinys, P., Dotson, D. L., Iwata, S., Beckstein, O., Cameron, A. D., and Drew, D. (2013) A two-domain elevator mechanism for sodium/proton antiport. Nature 501, 573-577
59. Wu, J., Petralia, R. S., Kurushima, H., Patel, H., Jung, M. Y., Volk, L., Chowdhury, S., Shepherd, J. D., Dehoff, M., Li, Y., Kuhl, D., Huganir, R. L., Price, D. L., Scannevin, R., Troncoso, J. C., Wong, P. C., and Worley, P. F. (2011) Arc/Arg3.1 regulates an endosomal pathway essential for activitydependent β-amyloid generation. Cell 147, 615-628
60. Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T. K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdhury, S., Worley, P. F., Steen, J., and Greenberg, M. E. (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140, 704-716
61. Brett, C. L., Donowitz, M., and Rao, R. (2005) Evolutionary origins of eukaryotic sodium/proton exchangers. Am. J. Physiol. Cell Physiol. 288, C223-239
62. Christianson, A. L., Stevenson, R. E., van der Meyden, C. H., Pelser, J., Theron, F. W., van Rensburg, P. L., Chandler, M., and Schwartz, C. E. (1999) X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27. J. Med. Genet. 36, 759-766
63. Naumova, O. Y., Palejev, D., Vlasova, N. V., Lee, M., Rychkov, S. Y., Babich, O. N. M. Vaccarino, F., and Grigorenko, E. L. (2012) Age-related changes of gene expression in the neocortex: preliminary data on RNA-Seq of the transcriptome in three functionally distinct cortical areas. Dev. Psychopathol. 24, 1427-1442
64. Coelho, L., Goertzel, B., Pennachin, C., and Heward, C. (2010) Classifier ensemble based analysis of a genome-wide SNP dataset concerning late-onset Alzheimer disease. Int. J. Software Sci. Comput. Intell. 10.4018/jssci.2010100105
65. Pérez-Palma, E., Bustos, B. I., Villamán, C. F., Alarcón, M. A., Avila, M. E., Ugarte, G. D., Reyes, A. E., Opazo, C., De Ferrari, G. V., Alzheimer's Disease Neuroimaging Initiative, and NIA-LOAD/NCRAD Family Study Group (2014) Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies. PloS One 9, e95413
66. Funk, K. E., and Kuret, J. (2012) Lysosomal fusion dysfunction as a unifying hypothesis for Alzheimer's disease pathology. Int. J. Alzheimers Dis. 2012, 752894
67. Cai, D., Leem, J. Y., Greenfield, J. P., Wang, P., Kim, B. S., Wang, R., Lopes, K. O., Kim, S. H., Zheng, H., Greengard, P., Sisodia, S. S., Thinakaran, G., and Xu, H. (2003) Presenilin-1 regulates intracellular trafficking and cell surface delivery of β-amyloid precursor protein. J. Biol. Chem. 278, 3446-3454
68. Saman, S., Kim, W., Raya, M., Visnick, Y., Miro, S., Saman, S., Jackson, B., McKee, A. C., Alvarez, V. E., Lee, N. C., and Hall, G. F. (2012) Exosomeassociated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 287, 3842-3849
69. Strømme, P., Dobrenis, K., Sillitoe, R. V., Gulinello, M., Ali, N. F., Davidson, C., Micsenyi, M. C., Stephney, G., Ellevog, L., Klungland, A., and Walkley, S. U. (2011) X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain 134, 3369-3383
70. +-ATPase inhibitor bafilomycin A1 differentially affects proteolytic processing of mutant and wild-type β-amyloid precursor protein. J. Biol. Chem. 270, 6186-6192
71. Knops, J., Suomensaari, S., Lee, M., McConlogue, L., Seubert, P., and Sinha, S. (1995) Cell-type and amyloid precursor protein-type specific inhibition of A β release by bafilomycin A1, a selective inhibitor of vacuolar ATPases. J. Biol. Chem. 270, 2419-2422
72. Schrader-Fischer, G., and Paganetti, P. A. (1996) Effect of alkalizing agents on the processing of the beta-amyloid precursor protein. Brain Res. 716, 91-100
73. Mitterreiter, S., Page, R. M., Kamp, F., Hopson, J., Winkler, E., Ha, H. R., Hamid, R., Herms, J., Mayer, T. U., Nelson, D. J., Steiner, H., Stahl, T., Zeitschel, U., Rossner, S., Haass, C., and Lichtenthaler, S. F. (2010) Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms. J. Neurosci. 30, 8974-8983
74. Yanai, I., Benjamin, H., Shmoish, M., Chalifa-Caspi, V., Shklar, M., Ophir, R., Bar-Even, A., Horn-Saban, S., Safran, M., Domany, E., Lancet, D., and Shmueli, O. (2005) Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics 21, 650-659
75. Kojetin, D. J., Thompson, R. J., and Cavanagh, J. (2003) Sub-classification of response regulators using the surface characteristics of their receiver domains. FEBS Lett. 554, 231-236