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Neurochemical Research

, Volume 39, Issue 3, pp 570–575 | Cite as

Cell Signaling Abnormalities May Drive Neurodegeneration in Familial Alzheimer Disease

  • Nikolaos K. RobakisEmail author
Overview

Abstract

Presenilins (PSs) are catalytic components of the γ-secretase complex that produces Aβ peptides. Substrates of γ-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived γ-secretase substrates are cleaved at gamma (γ) sites to produce Aβ while cleavage at the epsilon (ε) site produces AICD proposed to function in transcription. In addition to APP, γ-secretase promotes the ε-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling. A common hypothesis suggests that Alzheimer’s disease (AD) is caused by Aβ peptides or their products. Treatment of patients with inhibitors of Aβ production however, showed no therapeutic benefits while inducing cytotoxicity. Similarly, treatments with anti-Aβ antibodies yielded disappointing results. Importantly, recent evidence shows that PS familial AD (FAD) mutations cause a loss of γ-secretase cleavage activity at ε site of substrates thus inhibiting production of biologically important cell signaling peptides while promoting accumulation of membrane-bound cytotoxic substrates. These data support a hypothesis that FAD mutations may increase neurotoxicity by inhibiting the γ-secretase-catalyzed ε cleavage of substrates thus interfering with cell signaling while also promoting accumulation of cytotoxic peptides. Similar mechanisms may explain γ-secretase inhibitor-associated toxicities observed in clinical trials. Here we discuss evidence that FAD neurodegeneration may be caused by loss of γ-secretase cleavage function at ε sites of substrates.

Keywords

Epsilon cleavage γ-Secretase loss of function Signal transduction 

Notes

Acknowledgments

Supported by a grant from the AP Slaner family and NIH grant R37AG017926.

References

  1. 1.
    Anderson JP, Esch FS, Keim PS, Sambamurti K, Lieberburg I, Robakis NK (1991) Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci Lett 128:126–128PubMedCrossRefGoogle Scholar
  2. 2.
    Bai G, Chivatakarn O, Bonanomi D, Lettieri K, Franco L, Xia C, Stein E, Ma L, Lewcock JW, Pfaff SL (2011) Presenilin-dependent receptor processing is required for axon guidance. Cell 144:106–118PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Baki L, Neve RL, Shao Z, Shioi J, Georgakopoulos A, Robakis NK (2008) Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling. J Neurosci 28:483–490PubMedCrossRefGoogle Scholar
  4. 4.
    Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gama-Sosa M, Neve R, Robakis NK (2004) PS1 activates PI3 K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 23:2586–2596PubMedCrossRefGoogle Scholar
  5. 5.
    Barthet G et al (2011) Inhibitors of gamma-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. Faseb J 25:2937–2946PubMedCrossRefGoogle Scholar
  6. 6.
    Barthet G, Georgakopoulos A, Robakis NK (2012) Cellular mechanisms of γ-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166–175PubMedCrossRefGoogle Scholar
  7. 7.
    Batelli S, Albani D, Prato F, Polito L, Franceschi M, Gavazzi A, Forloni G (2008) Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394 V. Alzheimer Dis Assoc Disord 22:184–187PubMedCrossRefGoogle Scholar
  8. 8.
    Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B (2006) Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 96:732–742PubMedCrossRefGoogle Scholar
  9. 9.
    Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1–42/1–40 ratio in vitro and in vivo. Neuron 17:1005–1013PubMedCrossRefGoogle Scholar
  10. 10.
    Bouras C, Kovari E, Herrmann FR, Rivara CB, Bailey TL, von Gunten A, Hof PR, Giannakopoulos P (2006) Stereologic analysis of microvascular morphology in the elderly: Alzheimer disease pathology and cognitive status. J Neuropathol Exp Neurol 65:235–244PubMedCrossRefGoogle Scholar
  11. 11.
    Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J et al (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–846PubMedCrossRefGoogle Scholar
  12. 12.
    Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3:67–72PubMedCrossRefGoogle Scholar
  13. 13.
    Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 8:79–84PubMedCrossRefGoogle Scholar
  14. 14.
    Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, Masdeu J, Kawas C, Aronson M, Wolfson L (1988) Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology 38:1682–1687PubMedCrossRefGoogle Scholar
  15. 15.
    Cummings J (2010) What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer’s disease? Biol Psychiatry 68:876–878PubMedCrossRefGoogle Scholar
  16. 16.
    Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388PubMedCrossRefGoogle Scholar
  17. 17.
    Duering M, Grimm MO, Grimm HS, Schroder J, Hartmann T (2005) Mean age of onset in familial Alzheimer’s disease is determined by amyloid beta 42. Neurobiol Aging 26:785–788PubMedCrossRefGoogle Scholar
  18. 18.
    Fortini ME (2003) Neurobiology: double trouble for neurons. Nature 425:565–566PubMedCrossRefGoogle Scholar
  19. 19.
    Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK (2006) Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J 25:1242–1252PubMedCrossRefGoogle Scholar
  20. 20.
    Glenner GG, Wong CW (1987) Amyloidogenesis in Alzheimer’s disease and down’s syndrome. Banbury report 27: Mol. Neuropath of Aging. Cold Spring Harbor, Cold Spring Harbor Press, pp 253–265Google Scholar
  21. 21.
    Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223PubMedCrossRefGoogle Scholar
  22. 22.
    Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233PubMedCrossRefGoogle Scholar
  23. 23.
    Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA (2010) Alzheimer’s-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci USA 107:1630–1635PubMedCrossRefGoogle Scholar
  24. 24.
    Kang DE, Yoon IS, Repetto E, Busse T, Yermian N, Ie L, Koo EH (2005) Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem 280:31537–31547PubMedCrossRefGoogle Scholar
  25. 25.
    Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269:973–977PubMedCrossRefGoogle Scholar
  26. 26.
    Litterst C, Georgakopoulos A, Shioi J, Ghersi E, Wisniewski T, Wang R, Ludwig A, Robakis NK (2007) Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J Biol Chem 282:16155–16163PubMedCrossRefGoogle Scholar
  27. 27.
    Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, Salvesen GS, Koo EH, Bredesen DE (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat Med 6:397–404PubMedCrossRefGoogle Scholar
  28. 28.
    Marambaud P, Robakis NK (2005) Genetic and molecular aspects of Alzheimer’s disease shed light on new mechanisms of transcriptional regulation. Genes Brain Behav 4:134–146PubMedCrossRefGoogle Scholar
  29. 29.
    Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK (2003) A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635–645PubMedCrossRefGoogle Scholar
  30. 30.
    Miller DL, Papayannopoulos IA, Styles J, Bobin SA, Lin YY, Biemann K, Iqbal K (1993) Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys 301:41–52PubMedCrossRefGoogle Scholar
  31. 31.
    Mori H, Takio K, Ogawara M, Selkoe DJ (1992) Mass spectrometry of purified amyloid beta protein in Alzheimer’s disease. J Biol Chem 267:17082–17086PubMedGoogle Scholar
  32. 32.
    Newell KL, Hyman BT, Growdon JH, Hedley-Whyte ET (1999) Application of the National Institute on aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease. J Neuropathol Exp Neurol 58:1147–1155PubMedCrossRefGoogle Scholar
  33. 33.
    Neve RL, Robakis NK (1998) Alzheimer’s disease: a re-examination of the amyloid hypothesis. Trends Neurosci 21:15–19PubMedCrossRefGoogle Scholar
  34. 34.
    Pappolla MA, Omar RA, Kim KS, Robakis NK (1992) Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease. Am J Pathol 140:621–628PubMedGoogle Scholar
  35. 35.
    Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J (2003) Alzheimer’s presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci 23:4499–4508PubMedGoogle Scholar
  36. 36.
    Robakis NK (2011) Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging 32:372–379PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM (1987) Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci USA 84:4190–4194PubMedCrossRefGoogle Scholar
  38. 38.
    Robakis NK, Wisniewski HM, Jenkins EC, Devine-Gage EA, Houck GE, Yao XL, Ramakrishna N, Wolfe G, Silverman WP, Brown WT (1987) Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and down syndrome. Lancet 1:384–385PubMedCrossRefGoogle Scholar
  39. 39.
    Scheuermann S, Hambsch B, Hesse L, Stumm J, Schmidt C, Beher D, Bayer TA, Beyreuther K, Multhaup G (2001) Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer’s disease. J Biol Chem 276:33923–33929PubMedCrossRefGoogle Scholar
  40. 40.
    Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) 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. Nat Med 2:864–870PubMedCrossRefGoogle Scholar
  41. 41.
    Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Goate A, Wolfe MS, Shearman M, Kopan R (2003) A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci USA 100:13075–13080PubMedCrossRefGoogle Scholar
  42. 42.
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760PubMedCrossRefGoogle Scholar
  43. 43.
    Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK (2007) FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem 101:674–681PubMedCrossRefGoogle Scholar
  44. 44.
    Smith MA, Joseph JA, Perry G (2000) Arson. Tracking the culprit in Alzheimer’s disease. Ann N Y Acad Sci 924:35–38PubMedCrossRefGoogle Scholar
  45. 45.
    Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2 + leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126:981–993PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741PubMedCrossRefGoogle Scholar
  47. 47.
    Walsh DM, Klyubin I, Shankar GM, Townsend M, Fadeeva JV, Betts V, Podlisny MB, Cleary JP, Ashe KH, Rowan MJ, Selkoe DJ (2005) The role of cell-derived oligomers of Abeta in Alzheimer’s disease and avenues for therapeutic intervention. Biochem Soc Trans 33:1087–1090PubMedCrossRefGoogle Scholar
  48. 48.
    Weggen S, Rogers M, Eriksen J (2007) NSAIDs: small molecules for prevention of Alzheimer’s disease or precursors for future drug development? Trends Pharmacol Sci 28:536–543PubMedCrossRefGoogle Scholar
  49. 49.
    Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M (2005) Familial Alzheimer’s disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment. J Neurochem 94:1189–1201PubMedCrossRefGoogle Scholar
  50. 50.
    Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in down’s syndrome. Ann Neurol 17:278–282PubMedCrossRefGoogle Scholar
  51. 51.
    Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Departments of Psychiatry and Neuroscience, Mount Sinai School of MedicineNew York UniversityNew YorkUSA

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