Skip to main content
SpringerLink
Log in

Presenilin-Based Transgenic Models of Alzheimer’s Dementia

  • Protocol
  • First Online:
Animal Models of Dementia

Part of the book series: Neuromethods ((NM,volume 48))

  • 1372 Accesses

Abstract

Since the identification of the mutations in presenilin 1 and presenilin 2 genes more than a decade ago, a great deal of research has filled the gap in our knowledge of mutations underlying various phenotypes of Alzheimer’s disease (AD) that appear relatively early in the life of presenilin (PS) mutation carriers. Various molecular and cell biological techniques that showed functional differences between wild-type and mutant PS emerged during this time. In this chapter, we review this research by roughly categorizing findings that are similar or support a certain hypothesis. Sect. 1 discusses the function of PS as the component of γ-secretase, which generates amyloid β (Aβ). We also present a short history of how PS mutations were first considered to produce more Aβ42 (gain of function) and later found to produce less Aβ40, resulting in a higher Aβ42/Aβ40 ratio (loss as gain of function). This produces a condition in which Aβ is prone to aggregate, supporting the amyloid hypothesis of AD. Sect. 2 summarizes PS function vis-à-vis Notch signaling, which was identified by the gene-knockout approach. A hypothesis is discussed that suggests a partial loss of function, mainly based on various AD-like phenotypes observed in conditional double PS knockout mice. The first half of Sect. 3 is devoted to a review of various abnormalities related to the intracellular calcium regulation in cell and animal transgenic models of PS. The remainder of Sect. 3 discusses other potential mechanisms of PS dysfunction caused by mutations. These include abnormalities in protein trafficking, β-catenin/cadherin-related activities, and posttranslational modifications, the latter of which include endoproteolytic cleavage of PS itself, GSK-3β-dependent phosphorylation of tau, autophagy-based protein degradation, neprilysin-mediated Aβ metabolism, and alteration of unfolded protein response signaling. Any one or more of these PS dysfunctions may underlie the pathogenesis of familial AD and perhaps sporadic AD, if linked to mode of actions caused by nongenetic risk factors such as aging. Finally, we suggest the importance of bridging nonlinear dynamics of memory with molecular neuroscience of AD from multidimensional perspectives.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388

    Article  PubMed  CAS  Google Scholar 

  2. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  3. Goate A, Chartier-Harlin MC, Mullan M et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706

    Article  PubMed  CAS  Google Scholar 

  4. Suzuki N, Cheung TT, Cai XD et al (1994) An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (β APP717) mutants. Science 264:1336–1340

    Article  PubMed  CAS  Google Scholar 

  5. Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697

    Article  PubMed  CAS  Google Scholar 

  6. Jarrett JT, Lansbury PT Jr (1993) Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73:1055–1058

    Article  PubMed  CAS  Google Scholar 

  7. Iwatsubo T, Odaka A, Suzuki N et al (1994) Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 13:45–53

    Article  PubMed  CAS  Google Scholar 

  8. McGowan E, Pickford F, Kim J et al (2005) Aβ42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47:191–199

    Article  PubMed  CAS  Google Scholar 

  9. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44:181–193

    Article  PubMed  CAS  Google Scholar 

  10. Kayed R, Head E, Thompson JL et al (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–489

    Article  PubMed  CAS  Google Scholar 

  11. Schellenberg GD, Bird TD, Wijsman EM et al (1992) Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14. Science 258:668–671

    Article  PubMed  CAS  Google Scholar 

  12. Sherrington R, Rogaev EI, Liang Y et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760

    Article  PubMed  CAS  Google Scholar 

  13. Levy-Lahad E, Wijsman EM, Nemens E et al (1995) A familial Alzheimer’s disease locus on chromosome 1. Science 269:970–973

    Article  PubMed  CAS  Google Scholar 

  14. Levy-Lahad E, Wasco W, Poorkaj P et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977

    Article  PubMed  CAS  Google Scholar 

  15. Rogaev EI, Sherrington R, Rogaeva EA et al (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376:775–778

    Article  PubMed  CAS  Google Scholar 

  16. Duff K, Eckman C, Zehr C et al (1996) Increased Aβ42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713

    Article  PubMed  CAS  Google Scholar 

  17. Scheuner D, Eckman C, Jensen M et al (1996) Secreted amyloid β-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. Nat Med 2:864–870

    Article  PubMed  CAS  Google Scholar 

  18. Citron M, Westaway D, Xia W et al (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 3:67–72

    Article  PubMed  CAS  Google Scholar 

  19. Borchelt DR, Ratovitski T, van Lare J et al (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945

    Article  PubMed  CAS  Google Scholar 

  20. Dineley KT, Xia X, Bui D et al (2002) Accelerated plaque accumulation, associative learning deficits, and up-regulation of α 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J Biol Chem 277:22768–22780

    Article  PubMed  CAS  Google Scholar 

  21. Jankowsky JL, Fadale DJ, Anderson J et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum Mol Genet 13:159–170

    Article  PubMed  CAS  Google Scholar 

  22. De Strooper B, Saftig P, Craessaerts K et al (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390

    Article  PubMed  CAS  Google Scholar 

  23. Herreman A, Serneels L, Annaert W et al (2000) Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2:461–462

    Article  PubMed  CAS  Google Scholar 

  24. Herreman A, Hartmann D, Annaert W et al (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A 96:11872–11877

    Article  PubMed  CAS  Google Scholar 

  25. Zhang Z, Nadeau P, Song W et al (2000) Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2:463–465

    Article  PubMed  CAS  Google Scholar 

  26. Ancolio K, Dumanchin C, Barelli H et al (1999) Unusual phenotypic alteration of beta amyloid precursor protein (βAPP) maturation by a new Val-715 à Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci U S A 96:4119–4124

    Article  PubMed  CAS  Google Scholar 

  27. Murayama O, Tomita T, Nihonmatsu N et al (1999) Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett 265:61–63

    Article  PubMed  CAS  Google Scholar 

  28. Yoshiike Y, Chui DH, Akagi T et al (2003) Specific compositions of amyloid-β peptides as the determinant of toxic β-aggregation. J Biol Chem 278:23648–23655

    Article  PubMed  CAS  Google Scholar 

  29. Schroeter EH, Ilagan MX, Brunkan AL et al (2003) A presenilin dimer at the core of the γ-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A 100:13075–13080

    Article  PubMed  CAS  Google Scholar 

  30. Walker ES, Martinez M, Brunkan AL et al (2005) Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios. J Neurochem 92:294–301

    Article  PubMed  CAS  Google Scholar 

  31. Bentahir M, Nyabi O, Verhamme J et al (2006) Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 96:732–742

    Article  PubMed  CAS  Google Scholar 

  32. Kumar-Singh S, Theuns J, Van Broeck B et al (2006) Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40. Hum Mutat 27:686–695

    Article  PubMed  CAS  Google Scholar 

  33. Shimojo M, Sahara N, Murayama M et al (2007) Decreased Aβ secretion by cells expressing familial Alzheimer’s disease-linked mutant presenilin 1. Neurosci Res 57:446–453

    Article  PubMed  CAS  Google Scholar 

  34. Deng Y, Tarassishin L, Kallhoff V et al (2006) Deletion of presenilin 1 hydrophilic loop sequence leads to impaired γ-secretase activity and exacerbated amyloid pathology. J Neurosci 26:3845–3854

    Article  PubMed  CAS  Google Scholar 

  35. Wang R, Wang B, He W et al (2006) Wild-type presenilin 1 protects against Alzheimer disease mutation-induced amyloid pathology. J Biol Chem 281:15330–15336

    Article  PubMed  CAS  Google Scholar 

  36. Kim J, Onstead L, Randle S et al (2007) Aβ40 inhibits amyloid deposition in vivo. J Neurosci 27:627–633

    Article  PubMed  CAS  Google Scholar 

  37. Wolfe MS (2007) When loss is gain: reduced presenilin proteolytic function leads to increased Aβ42/Aβ40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8:136–140

    Article  PubMed  CAS  Google Scholar 

  38. De Strooper B (2007) Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8:141–146

    Article  PubMed  CAS  Google Scholar 

  39. Selkoe DJ, Wolfe MS (2007) Presenilin: running with scissors in the membrane. Cell 131:215–221

    Article  PubMed  CAS  Google Scholar 

  40. Marjaux E, Hartmann D, De Strooper B (2004) Presenilins in memory, Alzheimer’s disease, and therapy. Neuron 42:189–192

    Article  PubMed  CAS  Google Scholar 

  41. Shen J, Bronson RT, Chen DF et al (1997) Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89:629–639

    Article  PubMed  CAS  Google Scholar 

  42. Wong PC, Zheng H, Chen H et al (1997) Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387:288–292

    Article  PubMed  CAS  Google Scholar 

  43. Hartmann D, De Strooper B, Saftig P (1999) Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly. Curr Biol 9:719–727

    Article  PubMed  CAS  Google Scholar 

  44. Takahashi Y, Koizumi K, Takagi A et al (2000) Mesp2 initiates somite segmentation through the Notch signalling pathway. Nat Genet 25:390–396

    Article  PubMed  CAS  Google Scholar 

  45. Handler M, Yang X, Shen J (2000) Presenilin-1 regulates neuronal differentiation during neurogenesis. Development 127:2593–2606

    PubMed  CAS  Google Scholar 

  46. Nakajima M, Yuasa S, Ueno M et al (2003) Abnormal blood vessel development in mice lacking presenilin-1. Mech Dev 120:657–667

    Article  PubMed  CAS  Google Scholar 

  47. Donoviel DB, Hadjantonakis AK, Ikeda M et al (1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 13:2801–2810

    Article  PubMed  CAS  Google Scholar 

  48. Qyang Y, Chambers SM, Wang P et al (2004) Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of γ-secretase blockage. Biochemistry 43:5352–5359

    Article  PubMed  CAS  Google Scholar 

  49. Tournoy J, Bossuyt X, Snellinx A et al (2004) Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum Mol Genet 13:1321–1331

    Article  PubMed  CAS  Google Scholar 

  50. Xia X, Qian S, Soriano S et al (2001) Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A 98:10863–10868

    Article  PubMed  CAS  Google Scholar 

  51. Wang P, Pereira FA, Beasley D et al (2003) Presenilins are required for the formation of comma- and S-shaped bodies during nephrogenesis. Development 130:5019–5029

    Article  PubMed  CAS  Google Scholar 

  52. Yu H, Saura CA, Choi SY et al (2001) APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 31:713–726

    Article  PubMed  CAS  Google Scholar 

  53. Feng R, Rampon C, Tang YP et al (2001) Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32:911–926

    Article  PubMed  CAS  Google Scholar 

  54. Saura CA, Choi SY, Beglopoulos V et al (2004) Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42:23–36

    Article  PubMed  CAS  Google Scholar 

  55. Shen J, Kelleher RJ III (2007) The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A 104:403–409

    Article  PubMed  CAS  Google Scholar 

  56. Beglopoulos V, Sun X, Saura CA et al (2004) Reduced β-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem 279:46907–46914

    Article  PubMed  CAS  Google Scholar 

  57. Levitan D, Doyle TG, Brousseau D et al (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci U S A 93:14940–14944

    Article  PubMed  CAS  Google Scholar 

  58. Baumeister R, Leimer U, Zweckbronner I et al (1997) Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1:149–159

    Article  PubMed  CAS  Google Scholar 

  59. Wittenburg N, Eimer S, Lakowski B et al (2000) Presenilin is required for proper morphology and function of neurons in C. elegans. Nature 406:306–309

    Article  PubMed  CAS  Google Scholar 

  60. Davis JA, Naruse S, Chen H et al (1998) An Alzheimer’s disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 20:603–609

    Article  PubMed  CAS  Google Scholar 

  61. Qian S, Jiang P, Guan XM et al (1998) Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1–42/43 expression. Neuron 20:611–617

    Article  PubMed  CAS  Google Scholar 

  62. Janus C, D’Amelio S, Amitay O et al (2000) Spatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes. Neurobiol Aging 21:541–549

    Article  PubMed  CAS  Google Scholar 

  63. Wang R, Dineley KT, Sweatt JD et al (2004) Presenilin 1 familial Alzheimer’s disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience 126:305–312

    Article  PubMed  CAS  Google Scholar 

  64. Dewachter I, Reversé D, Caluwaerts N et al (2002) Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci 22:3445–3453

    PubMed  CAS  Google Scholar 

  65. Saura CA, Chen G, Malkani S et al (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25:6755–6764

    Article  PubMed  CAS  Google Scholar 

  66. Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6:337–350

    Article  PubMed  CAS  Google Scholar 

  67. Guo Q, Fu W, Sopher BL et al (1999) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5:101–106

    Article  PubMed  CAS  Google Scholar 

  68. Begley JG, Duan W, Chan S et al (1999) Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem 72:1030–1039

    Article  PubMed  CAS  Google Scholar 

  69. Barrow PA, Empson RM, Gladwell SJ et al (2000) Functional phenotype in transgenic mice expressing mutant human presenilin-1. Neurobiol Dis 7:119–126

    Article  PubMed  CAS  Google Scholar 

  70. Grilli M, Diodato E, Lozza G et al (2000) Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically. Proc Natl Acad Sci U S A 97:12822–12827

    Article  PubMed  CAS  Google Scholar 

  71. Schneider I, Reverse D, Dewachter I et al (2001) Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem 276:11539–11544

    Article  PubMed  CAS  Google Scholar 

  72. Leissring MA, Akbari Y, Fanger CM et al (2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149:793–798

    Article  PubMed  CAS  Google Scholar 

  73. Yoo AS, Cheng I, Chung S et al (2000) Presenilin-mediated modulation of capacitative calcium entry. Neuron 27:561–572

    Article  PubMed  CAS  Google Scholar 

  74. Stutzmann GE, Smith I, Caccamo A et al (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci 26:5180–5189

    Article  PubMed  CAS  Google Scholar 

  75. Tu H, Nelson O, Bezprozvanny A et al (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126:981–993

    Article  PubMed  CAS  Google Scholar 

  76. Nelson O, Tu H, Lei T et al (2007) Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest 117:1230–1239

    Article  PubMed  CAS  Google Scholar 

  77. Palop JJ, Chin J, Roberson ED et al (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55:697–711

    Article  PubMed  CAS  Google Scholar 

  78. Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-β. Nat Neurosci 8:1051–1058

    Article  PubMed  CAS  Google Scholar 

  79. Parsons CG, Stöffler A, Danysz W (2007) Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system-too little activation is bad, too much is even worse. Neuropharmacology 53:699–723

    Article  PubMed  CAS  Google Scholar 

  80. Thinakaran G, Borchelt DR, Lee MK et al (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17:181–190

    Article  PubMed  CAS  Google Scholar 

  81. Lee MK, Borchelt DR, Kim G et al (1997) Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med 3:756–760

    Article  PubMed  CAS  Google Scholar 

  82. Naruse S, Thinakaran G, Luo JJ et al (1998) Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21:1213–1221

    Article  PubMed  CAS  Google Scholar 

  83. Cai D, Leem JY, Greenfield JP et al (2003) Presenilin-1 regulates intracellular trafficking and cell surface delivery of β-amyloid precursor protein. J Biol Chem 278:3446–3454

    Article  PubMed  CAS  Google Scholar 

  84. Wang R, Tang P, Wang P et al (2006) Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer’s disease mutation. Proc Natl Acad Sci U S A 103:353–358

    Article  PubMed  CAS  Google Scholar 

  85. Zhang Z, Hartmann H, Do VM et al (1998) Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395:698–702

    Article  PubMed  CAS  Google Scholar 

  86. Kang DE, Soriano S, Xia X et al (2002) Presenilin couples the paired phosphorylation of β-catenin independent of axin: implications for β-catenin activation in tumorigenesis. Cell 110:751–762

    Article  PubMed  CAS  Google Scholar 

  87. Marambaud P, Wen PH, Dutt A et al (2003) A CBP binding transcriptional repressor ­produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635–645

    Article  PubMed  CAS  Google Scholar 

  88. Takashima A, Murayama M, Murayama O et al (1998) Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau. Proc Natl Acad Sci U S A 95:9637–9641

    Article  PubMed  CAS  Google Scholar 

  89. Baki L, Shioi J, Wen P et al (2004) PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 23:2586–2596

    Article  PubMed  CAS  Google Scholar 

  90. Tanemura K, Chui DH, Fukuda T et al (2006) Formation of tau inclusions in knock-in mice with familial Alzheimer disease (FAD) mutation of presenilin 1 (PS1). J Biol Chem 281:5037–5041

    Article  PubMed  CAS  Google Scholar 

  91. Braak H, Braak E, Bohl J (1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33:403–408

    Article  PubMed  CAS  Google Scholar 

  92. Nakano Y, Kondoh G, Kudo T et al (1999) Accumulation of murine amyloidβ42 in a gene-dosage-dependent manner in PS1 ‘knock-in’ mice. Eur J Neurosci 11:2577–2581

    Article  PubMed  CAS  Google Scholar 

  93. Annaert WG, Esselens C, Baert V et al (2001) Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron 32:579–589

    Article  PubMed  CAS  Google Scholar 

  94. Esselens C, Oorschot V, Baert V et al (2004) Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol 166:1041–1054

    Article  PubMed  CAS  Google Scholar 

  95. Iwata N, Tsubuki S, Takaki Y et al (2001) Metabolic regulation of brain Aβ by neprilysin. Science 292:1550–1552

    Article  PubMed  CAS  Google Scholar 

  96. Pardossi-Piquard R, Dunys J, Kawarai T et al (2005) Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP. Neuron 46:541–554

    Article  PubMed  CAS  Google Scholar 

  97. Chen AC, Selkoe DJ (2007) Response to: Pardossi-Piquard et al., “Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP.” Neuron 46:541–554. Neuron 53:479–483

    Article  PubMed  CAS  Google Scholar 

  98. Pardossi-Piquard R, Dunys J, Kawarai T et al (2007) Response to correspondence: Pardossi-Piquard et al., “Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP.” Neuron 46, 541–554. Neuron 53:483–486

    Article  PubMed  CAS  Google Scholar 

  99. Katayama T, Imaizumi K, Sato N et al (1999) Presenilin-1 mutations downregulate the ­signalling pathway of the unfolded-protein response. Nat Cell Biol 1:479–485

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lab. for Alzheimer’s Disease, RIKEN Brain Science Institute, Saitama, Japan

    Yuji Yoshiike & Akihiko Takashima

Authors
  1. Yuji Yoshiike
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akihiko Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute Born-Bunge, Lab of Neurochemistry & Behaviour, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Peter Paul De Deyn

  2. Institute Born-Bunge, Lab of Neurochemistry & Behaviour, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Debby Van Dam

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Yoshiike, Y., Takashima, A. (2011). Presenilin-Based Transgenic Models of Alzheimer’s Dementia. In: De Deyn, P., Van Dam, D. (eds) Animal Models of Dementia. Neuromethods, vol 48. Humana Press. https://doi.org/10.1007/978-1-60761-898-0_21

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-898-0_21

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-897-3

  • Online ISBN: 978-1-60761-898-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation