IRE1 signaling exacerbates Alzheimer’s disease pathogenesis

Acta Neuropathologica

Volumn 134, Issue 3, 2017, Pages 489-506

  Duran Aniotz, Claudia ^a,b,c   Cornejo, Victor Hugo ^a,b,c   Espinoza, Sandra ^a,b,c   Ardiles, Álvaro O ^d   Medinas, Danilo B ^a,b,c   Salazar, Claudia ^d   Foley, Andrew ^a,c   Gajardo, Ivana ^d   Thielen, Peter ^e   Iwawaki, Takao ^f   Scheper, Wiep ^h,i   Soto, Claudio ^g   Palacios, Adrian G ^d   Hoozemans, Jeroen J M ^j   Hetz, Claudio ^a,b,c,e,k  

^a UNIVERSITY OF CHILE   (Chile)

^b Universidad de Chile and Geroscience Center for Brain Health and Metabolism   (Chile)

^c UNIVERSITY OF CHILE   (Chile)

^d UNIVERSIDAD DE VALPARAÍSO   (Chile)

^e HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^f KANAZAWA MEDICAL UNIVERSITY   (Japan)

^g UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^h VU UNIVERSITY MEDICAL CENTER   (Netherlands)

ⁱ VU UNIVERSITY AMSTERDAM   (Netherlands)

^j VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^k BUCK INSTITUTE FOR RESEARCH ON AGING   (United States)

more..

Author keywords

Alzheimer s disease; Amyloid ; Endoplasmic reticulum stress; Proteostasis impairment; Unfolded protein response; UPR

Indexed keywords

AMYLOID; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; OLIGOMER; PROTEASOME; PROTEIN IRE1; RIBONUCLEASE; ERN2 PROTEIN, MOUSE; MEMBRANE PROTEIN; PROTEIN SERINE THREONINE KINASE;

ADULT; AGED; ALZHEIMER DISEASE; AMNESIA; ARTICLE; ASTROCYTE; BRAIN CORTEX; BRAIN FUNCTION; BRAIN TISSUE; CLINICAL ARTICLE; CONTROLLED STUDY; CORRELATIONAL STUDY; DISEASE COURSE; DISEASE EXACERBATION; FEMALE; HIPPOCAMPUS; HISTOPATHOLOGY; HUMAN; HUMAN TISSUE; IN VITRO STUDY; LONG TERM POTENTIATION; MALE; MIDDLE AGED; MOUSE; NEUROPATHOLOGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; TRANSGENIC MOUSE; UNFOLDED PROTEIN RESPONSE; VERY ELDERLY; ANIMAL; DISEASE MODEL; ENDOPLASMIC RETICULUM STRESS; GENETICS; METABOLISM; NERVE CELL; PATHOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION; SPATIAL MEMORY;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; AMYLOID BETA-PROTEIN PRECURSOR; ANIMALS; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; ENDOPLASMIC RETICULUM STRESS; HIPPOCAMPUS; HUMANS; LONG-TERM POTENTIATION; MEMBRANE PROTEINS; MICE; MICE, TRANSGENIC; NEURONS; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION; SPATIAL MEMORY; UNFOLDED PROTEIN RESPONSE;

EID: 85016059001     PISSN: 00016322     EISSN: 14320533     Source Type: Journal    
DOI: 10.1007/s00401-017-1694-x     Document Type: Article

References (103)

1. Abisambra JF, Jinwal UK, Blair LJ et al (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33:9498–9507. doi:10.1523/JNEUROSCI.5397-12.2013
2. Acosta-Alvear D, Zhou Y, Blais A et al (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27:53–66. doi:10.1016/j.molcel.2007.06.011
3. Alafuzoff I, Pikkarainen M, Neumann M et al (2015) Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium. J Neural Transm (Vienna) 122:957–972. doi:10.1007/s00702-014-1304-1
4. Ballard C, Gauthier S, Corbett A et al (2011) Alzheimer’s disease. Lancet 377:1019–1031. doi:10.1016/S0140-6736(10)61349-9
5. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
6. Burgos PV, Mardones GA, Rojas AL et al (2010) Sorting of the Alzheimer’s disease amyloid precursor protein mediated by the AP-4 complex. Dev Cell 18:425–436. doi:10.1016/j.devcel.2010.01.015
7. Calfon M, Zeng H, Urano F et al (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415:92–96. doi:10.1038/415092a
8. Casas-Tinto S, Zhang Y, Sanchez-Garcia J et al (2011) The ER stress factor XBP1 s prevents amyloid-beta neurotoxicity. Hum Mol Genet 20:2144–2160. doi:10.1093/hmg/ddr100
9. Cescon M, Chen P, Castagnaro S, Gregorio I, Bonaldo P (2016) Lack of collagen VI promotes neurodegeneration by impairing autophagy and inducing apoptosis during aging. Aging (Albany NY) 8:1083–1101. doi:10.18632/aging.100924
10. Chen X, Iliopoulos D, Zhang Q et al (2014) XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature 508:103–107. doi:10.1038/nature13119
11. Cheng JS, Dubal DB, Kim DH et al (2009) Collagen VI protects neurons against Abeta toxicity. Nat Neurosci 12:119–121. doi:10.1038/nn.2240
12. Clayton BL, Popko B (2016) Endoplasmic reticulum stress and the unfolded protein response in disorders of myelinating glia. Brain Res 1:594–602. doi:10.1016/j.brainres.2016.03.046
13. Cornejo VH, Hetz C (2013) The unfolded protein response in Alzheimer’s disease. Semin Immunopathol 35:277–292. doi:10.1007/s00281-013-0373-9
14. Cornejo VH, Pihan P, Vidal RL, Hetz C (2013) Role of the unfolded protein response in organ physiology: lessons from mouse models. IUBMB Life 65:962–975. doi:10.1002/iub.1224
15. Costa-Mattioli M, Gobert D, Harding H et al (2005) Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436:1166–1173. doi:10.1038/nature03897
16. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N (2009) Translational control of long-lasting synaptic plasticity and memory. Neuron 61:10–26. doi:10.1016/j.neuron.2008.10.055
17. Cuanalo-Contreras K, Mukherjee A, Soto C (2013) Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. Int J Cell Biol 2013:638083. doi:10.1155/2013/638083
18. Devi L, Ohno M (2013) Deletion of the eIF2alpha Kinase GCN2 fails to rescue the memory decline associated with Alzheimer’s disease. PLoS OnE 8:e77335. doi:10.1371/journal.pone.0077335
19. Devi L, Ohno M (2014) PERK mediates eIF2alpha phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer’s disease. Neurobiol Aging 35:2272–2281. doi:10.1016/j.neurobiolaging.2014.04.031
20. Douglas PM, Dillin A (2010) Protein homeostasis and aging in neurodegeneration. J Cell Biol 190:719–729. doi:10.1083/jcb.201005144
21. Du J, Duan S, Wang H et al (2008) Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia. J Neural Transm 115:513–519. doi:10.1007/s00702-007-0844-z
22. Duran-Aniotz C, Martinez G, Hetz C (2014) Memory loss in Alzheimer’s disease: are the alterations in the UPR network involved in the cognitive impairment? Front Aging Neurosci 6:8. doi:10.3389/fnagi.2014.00008
23. Duran-Aniotz C, Morales R, Moreno-Gonzalez I et al (2014) Aggregate-depleted brain fails to induce Abeta deposition in a mouse model of Alzheimer’s disease. PLoS One 9:e89014. doi:10.1371/journal.pone.0089014
24. Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP, Soto C (2013) Brains from non-Alzheimer’s individuals containing amyloid deposits accelerate Abeta deposition in vivo. Acta Neuropathol Commun 1:76. doi:10.1186/2051-5960-1-76
25. Eimer WA, Vassar R (2013) Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation. Mol Neurodegener 8:2. doi:10.1186/1750-1326-8-2
26. Freeman OJ, Mallucci GR (2016) The UPR and synaptic dysfunction in neurodegeneration. Brain Res 1:530–537. doi:10.1016/j.brainres.2016.03.029
27. Gambella M, Rocci A, Passera R et al (2014) High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib. Haematologica 99:e14–16. doi:10.3324/haematol.2013.090142
28. Ghosh R, Wang L, Wang ES et al (2014) Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534–548. doi:10.1016/j.cell.2014.07.002
29. Granger AJ, Nicoll RA (2014) Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on. Philos Trans R Soc Lond B Biol Sci 369:20130136. doi:10.1098/rstb.2013.0136
30. Han D, Lerner AG, Vande Walle L et al (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562–575. doi:10.1016/j.cell.2009.07.017
31. Hetz C, Chevet E, Harding HP (2013) Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12:703–719. doi:10.1038/nrd3976
32. Hetz C, Chevet E, Oakes SA (2015) Proteostasis control by the unfolded protein response. Nat Cell Biol 17:829–838. doi:10.1038/ncb3184
33. Hetz C, Lee AH, Gonzalez-Romero D et al (2008) Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc Natl Acad Sci USA 105:757–762. doi:10.1073/pnas.0711094105
34. Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249. doi:10.1038/nrn3689
35. Hetz C, Thielen P, Matus S et al (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306. doi:10.1101/gad.1830709
36. Hollien J, Lin JH, Li H et al (2009) Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 186:323–331. doi:10.1083/jcb.200903014
37. Hoozemans JJ, van Haastert ES, Nijholt DA et al (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241–1251. doi:10.2353/ajpath.2009.080814
38. Hu Y, Park KK, Yang L et al (2012) Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron 73:445–452. doi:10.1016/j.neuron.2011.11.026
39. Iwawaki T, Akai R, Kohno K (2010) IRE1alpha disruption causes histological abnormality of exocrine tissues, increase of blood glucose level, and decrease of serum immunoglobulin level. PLoS One 5:e13052. doi:10.1371/journal.pone.0013052
40. Iwawaki T, Akai R, Yamanaka S, Kohno K (2009) Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci USA 106:16657–16662. doi:10.1073/pnas.0903775106
41. Jiang Z, Belforte JE, Lu Y et al (2010) eIF2alpha Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. J Neurosci 30:2582–2594. doi:10.1523/JNEUROSCI.3971-09.2010
42. Kakiuchi C, Iwamoto K, Ishiwata M et al (2003) Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35:171–175. doi:10.1038/ng1235
43. Kaushik S, Cuervo AM (2015) Proteostasis and aging. Nat Med 21:1406–1415. doi:10.1038/nm.4001
44. Kennedy BK, Berger SL, Brunet A et al (2014) Geroscience: linking aging to chronic disease. Cell 159:709–713. doi:10.1016/j.cell.2014.10.039
45. Kim B, Kim CY, Lee MJ, Joo YH (2009) Preliminary evidence on the association between XBP1-116C/G polymorphism and response to prophylactic treatment with valproate in bipolar disorders. Psychiatry Res 168:209–212. doi:10.1016/j.psychres.2008.05.010
46. Kondo T, Asai M, Tsukita K et al (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular abeta and differential drug responsiveness. Cell Stem Cell 4:487–496. doi:10.1016/j.stem.2013.01.009
47. Labbadia J, Morimoto RI (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435–464. doi:10.1146/annurev-biochem-060614-033955
48. Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:7448–7459
49. Lee JH, Won SM, Suh J et al (2010) Induction of the unfolded protein response and cell death pathway in Alzheimer’s disease, but not in aged Tg2576 mice. Exp Mol Med 42:386–394
50. Lee JH, Yu WH, Kumar A et al (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141:1146–1158. doi:10.1016/j.cell.2010.05.008
51. Lee K, Tirasophon W, Shen X et al (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16:452–466. doi:10.1101/gad.964702
52. Lerner AG, Upton JP, Praveen PV et al (2012) IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 16:250–264. doi:10.1016/j.cmet.2012.07.007
53. Loewen CA, Feany MB (2010) The unfolded protein response protects from tau neurotoxicity in vivo. PLoS One 5:e13084. doi:10.1371/journal.pone.0013084
54. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. doi:10.1016/j.cell.2013.05.039
55. Lourenco MV, Clarke JR, Frozza RL et al (2013) TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s beta-amyloid oligomers in mice and monkeys. Cell Metab 18:831–843. doi:10.1016/j.cmet.2013.11.002
56. Ma T, Trinh MA, Wexler AJ et al (2013) Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci 16:1299–1305. doi:10.1038/nn.3486
57. Maly DJ, Papa FR (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892–901. doi:10.1038/nchembio.1664
58. Martinez G, Vidal RL, Mardones P et al (2016) Regulation of Memory Formation by the Transcription Factor XBP1. Cell Rep 16:1382–1394. doi:10.1016/j.celrep.2016.01.028
59. Maurel M, Chevet E, Tavernier J, Gerlo S (2014) Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci 39:245–254. doi:10.1016/j.tibs.2014.02.008
60. Medinas DB, Hetz C (2013) Proteostasis impairment: at the intersection between Alzheimer’s disease and diabetes. Cell Metab 18:771–772. doi:10.1016/j.cmet.2013.11.009
61. Moreno JA, Halliday M, Molloy C et al (2013) Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 5:206ra138. doi:10.1126/scitranslmed.3006767
62. Moreno JA, Radford H, Peretti D et al (2012) Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature 485:507–511. doi:10.1038/nature11058
63. Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226:693–702. doi:10.1002/path.3969
64. O’Connor T, Sadleir KR, Maus E et al (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60:988–1009. doi:10.1016/j.neuron.2008.10.047
65. Oakes SA, Papa FR (2015) The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol 10:173–194. doi:10.1146/annurev-pathol-012513-104649
66. Oakley H, Cole SL, Logan S et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140. doi:10.1523/JNEUROSCI.1202-06.2006
67. Ohno M, Chang L, Tseng W et al (2006) Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23:251–260. doi:10.1111/j.1460-9568.2005.04551.x
68. Ohno M, Cole SL, Yasvoina M et al (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26:134–145. doi:10.1016/j.nbd.2006.12.008
69. Onate M, Catenaccio A, Martinez G et al (2016) Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury. Sci Rep 6:21709. doi:10.1038/srep21709
70. Peng Y, Kim MJ, Hullinger R et al (2016) Improved proteostasis in the secretory pathway rescues Alzheimer’s disease in the mouse. Brain 139:937–952. doi:10.1093/brain/awv385
71. Placido AI, Pereira CM, Duarte AI et al (2014) The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: implications for Alzheimer’s disease. Biochim Biophys Acta 1842:1444–1453. doi:10.1016/j.bbadis.2014.05.003
72. Pluquet O, Dejeans N, Bouchecareilh M et al (2013) Posttranscriptional regulation of PER1 underlies the oncogenic function of IREalpha. Cancer Res 73:4732–4743. doi:10.1158/0008-5472.CAN-12-3989
73. Ramirez O, Garcia A, Rojas R, Couve A, Hartel S (2010) Confined displacement algorithm determines true and random colocalization in fluorescence microscopy. J Microsc 239:173–183. doi:10.1111/j.1365-2818.2010.03369.x
74. Reimold AM, Etkin A, Clauss I et al (2000) An essential role in liver development for transcription factor XBP-1. Genes Dev 14:152–157
75. Reinhardt S, Schuck F, Grosgen S et al (2014) Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer’s disease. FASEB J 28:978–997. doi:10.1096/fj.13-234864
76. Sado M, Yamasaki Y, Iwanaga T et al (2009) Protective effect against Parkinson’s disease-related insults through the activation of XBP1. Brain Res 1257:16–24. doi:10.1016/j.brainres.2008.11.104
77. Scheper W, Hoozemans JJ (2015) The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol 130:315–331. doi:10.1007/s00401-015-1462-8
78. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113. doi:10.1016/j.bbr.2008.02.016
79. Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842. doi:10.1038/nm1782
80. Smith HL, Mallucci GR (2016) The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain 139:2113–2121. doi:10.1093/brain/aww101
81. Song Y, Sretavan D, Salegio EA et al (2015) Regulation of axon regeneration by the RNA repair and splicing pathway. Nat Neurosci 18:817–825. doi:10.1038/nn.4019
82. Stutzbach LD, Xie SX, Naj AC et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. doi:10.1186/2051-5960-1-31
83. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800
84. Trinh MA, Kaphzan H, Wek RC et al (2012) Brain-specific disruption of the eIF2alpha kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep 1:676–688. doi:10.1016/j.celrep.2012.04.010
85. Trinh MA, Ma T, Kaphzan H et al (2014) The eIF2alpha kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression. Learn Mem 21:298–304. doi:10.1101/lm.032219.113
86. Uchihara T (2007) Silver diagnosis in neuropathology: principles, practice and revised interpretation. Acta Neuropathol 113:483–499. doi:10.1007/s00401-007-0200-2
87. Unterberger U, Hoftberger R, Gelpi E et al (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65:348–357. doi:10.1097/01.jnen.0000218445.30535.6f
88. Upton JP, Wang L, Han D et al (2012) IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338:818–822. doi:10.1126/science.1226191
89. Urra H, Dufey E, Lisbona F, Rojas-Rivera D, Hetz C (2013) When ER stress reaches a dead end. Biochim Biophys Acta 1833:3507–3517. doi:10.1016/j.bbamcr.2013.07.024
90. Valdes P, Mercado G, Vidal RL et al (2014) Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc Natl Acad Sci USA 111:6804–6809. doi:10.1073/pnas.1321845111
91. Valenzuela V, Collyer E, Armentano D et al (2012) Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis 3:e272. doi:10.1038/cddis.2012.8
92. Verwey NA, Hoozemans JJ, Korth C et al (2013) Immunohistochemical characterization of novel monoclonal antibodies against the N-terminus of amyloid beta-peptide. Amyloid 20:179–187. doi:10.3109/13506129.2013.797389
93. Viana RJ, Nunes AF, Rodrigues CM (2012) Endoplasmic reticulum enrollment in Alzheimer’s Disease. Mol Neurobiol 46:522–534. doi:10.1007/s12035-012-8301-x
94. Vidal RL, Figueroa A, Court FA et al (2012) Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 21:2245–2262. doi:10.1093/hmg/dds040
95. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858. doi:10.1038/nprot.2006.116
96. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086. doi:10.1126/science.1209038
97. Wang M, Kaufman RJ (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529:326–335. doi:10.1038/nature17041
98. Xu T, Yang L, Yan C et al (2014) The IRE1alpha-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic beta-cells. Cell Res 24:1137–1140. doi:10.1038/cr.2014.55
99. Yang DS, Stavrides P, Mohan PS et al (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 134:258–277. doi:10.1093/brain/awq341
100. Yang DS, Stavrides P, Saito M et al (2014) Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 137:3300–3318. doi:10.1093/brain/awu278
101. Yang J, Cheng D, Zhou S et al (2015) Overexpression of X-Box binding protein 1 (XBP1) correlates to poor prognosis and Up-regulation of PI3 K/mTOR in human osteosarcoma. Int J Mol Sci 16:28635–28646. doi:10.3390/ijms161226123
102. Yang W, Zhou X, Zimmermann HR et al (2016) Repression of the eIF2alpha kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer’s disease. Neurobiol Aging 41:19–24. doi:10.1016/j.neurobiolaging.2016.02.005
103. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891