Acta Neuropathologica

, Volume 124, Issue 6, pp 809–821 | Cite as

APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38

  • Maria Luisa Moro
  • Giorgio Giaccone
  • Raffaella Lombardi
  • Antonio Indaco
  • Andrea Uggetti
  • Michela Morbin
  • Stefania Saccucci
  • Giuseppe Di Fede
  • Marcella Catania
  • Dominic M. Walsh
  • Andrea Demarchi
  • Annemieke Rozemuller
  • Nenad Bogdanovic
  • Orso Bugiani
  • Bernardino Ghetti
  • Fabrizio Tagliavini
Original Paper


Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.


Aβ38 Alzheimer’s disease Familial disease Amyloid Immunohistochemistry 


  1. 1.
    Alafuzoff I, Pikkarainen M, Arzberger T et al (2008) Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein: a study of the BrainNet Europe consortium. Acta Neuropathol 115:533–546PubMedCrossRefGoogle Scholar
  2. 2.
    Basun H, Bogdanovic N, Ingelsson M et al (2008) Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol 65:499–505PubMedCrossRefGoogle Scholar
  3. 3.
    Bentahir M, Nyabi O, Verhamme J et al (2006) Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 96:732–742PubMedCrossRefGoogle Scholar
  4. 4.
    Bettens K, Sleegers K, Van Broeckhoven C (2010) Current status on Alzheimer disease molecular genetics: from past, to present, to future. Hum Mol Genet 19:R4–R11PubMedCrossRefGoogle Scholar
  5. 5.
    Bruni AC, Bernardi L, Colao R et al (2010) Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation. Neurology 74:798–806PubMedCrossRefGoogle Scholar
  6. 6.
    Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O (2012) Cerebrospinal fluid levels of β-amyloid 1–42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 69:98–106PubMedCrossRefGoogle Scholar
  7. 7.
    Bugiani O, Giaccone G, Rossi G et al (2010) Hereditary cerebral hemorrhage with amyloidosis associated with the E693K mutation of APP. Arch Neurol 67:987–995PubMedCrossRefGoogle Scholar
  8. 8.
    Chávez-Gutiérrez L, Bammens L, Benilova I et al (2012) The mechanism of γ-secretase dysfunction in familial Alzheimer disease. EMBO J 31:2261–2274PubMedCrossRefGoogle Scholar
  9. 9.
    Cupidi C, Capobianco R, Goffredo D et al (2010) Neocortical variation of Aβ load in fully expressed, pure Alzheimer disease. J Alzheimer Dis 19:57–68Google Scholar
  10. 10.
    Czirr E, Cottrell BA, Leuchtenberger S et al (2008) Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase. J Biol Chem 283:17049–17054PubMedCrossRefGoogle Scholar
  11. 11.
    Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277:32046–32053PubMedCrossRefGoogle Scholar
  12. 12.
    Di Fede G, Catania M, Morbin M et al (2009) A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science 323:1473–1477PubMedCrossRefGoogle Scholar
  13. 13.
    Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–11127PubMedCrossRefGoogle Scholar
  14. 14.
    Duyckaerts C, Potier MC, Delatour B (2008) Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 115:5–38PubMedCrossRefGoogle Scholar
  15. 15.
    Gallo M, Marcello N, Curcio SA et al (2011) A novel pathogenic PSEN1 mutation in a family with Alzheimer’s disease: phenotypical and neuropathological features. J Alzheimers Dis 25:425–431PubMedGoogle Scholar
  16. 16.
    Giaccone G, Arzberger T, Alafuzoff I et al (2011) BrainNet Europe consortium. New lexicon and criteria for the diagnosis of Alzheimer’s disease. Lancet Neurol. 10:298–299PubMedCrossRefGoogle Scholar
  17. 17.
    Giaccone G, Morbin M, Moda F et al (2010) Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features. Acta Neuropathol 120:803–812PubMedCrossRefGoogle Scholar
  18. 18.
    Giaccone G, Tagliavini F, Linoli G et al (1989) Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci Lett 97:232–238PubMedCrossRefGoogle Scholar
  19. 19.
    Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci 83:4913–4917PubMedCrossRefGoogle Scholar
  20. 20.
    Hellström-Lindah E, Viitanen M, Marutle A (2009) Comparison of Abeta levels in the brain of familial and sporadic Alzheimer’s disease. Neurochem Int 55:243–252CrossRefGoogle Scholar
  21. 21.
    Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697PubMedCrossRefGoogle Scholar
  22. 22.
    Kukar TL, Ladd TB, Robertson P et al (2011) Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid β peptide length: support for a sequential model of γ-secretase intramembrane proteolysis and regulation by the amyloid β precursor protein (APP) juxtamembrane region. J Biol Chem 286:39804–39812PubMedCrossRefGoogle Scholar
  23. 23.
    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 Abeta42 and decreased Abeta40. Hum Mutat 27:686–695PubMedCrossRefGoogle Scholar
  24. 24.
    Levy E, Carman MD, Fernandez-Madrid IJ et al (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126PubMedCrossRefGoogle Scholar
  25. 25.
    Lue LF, Kuo YM, Roher AE et al (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862PubMedCrossRefGoogle Scholar
  26. 26.
    Maler JM, Klafki HW, Paul S et al (2007) Urea-based two-dimensional electrophoresis of beta-amyloid peptides in human plasma: evidence for novel Abeta species. Proteomics 7:3815–3820PubMedCrossRefGoogle Scholar
  27. 27.
    Marcon G, Giaccone G, Cupidi C et al (2004) Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol 63:199–209PubMedGoogle Scholar
  28. 28.
    McDonald JM, Cairns NJ, Taylor-Reinwald L, Holtzman D, Walsh DM (2012) The levels of water-soluble and triton-soluble Aβ are increased in Alzheimer’s disease brain. Brain Res 1450:138–147PubMedCrossRefGoogle Scholar
  29. 29.
    Mc Donald JM, Savva GM, Brayne C et al (2010) Medical Research Council Cognitive Function and Ageing Study. The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain 133:1328–1341Google Scholar
  30. 30.
    Munter LM, Botev A, Richter L et al (2010) Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif. J Biol Chem 285:21636–21643PubMedCrossRefGoogle Scholar
  31. 31.
    Munter LM, Voigt P, Harmeier A et al (2007) GxxxG motifs within the amyloid precursorprotein transmembrane sequence are critical for the etiology of Abeta42. EMBO J 26:1702–1712PubMedCrossRefGoogle Scholar
  32. 32.
    Murrell J, Farlow M, Ghetti B, Benson MD (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254:97–99PubMedCrossRefGoogle Scholar
  33. 33.
    Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B (2000) Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol 57:885–887PubMedCrossRefGoogle Scholar
  34. 34.
    Obici L, Demarchi A, de Rosa G et al (2005) A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol 58:639–644PubMedCrossRefGoogle Scholar
  35. 35.
    Patterson D (2009) Molecular genetic analysis of Down syndrome. Hum Genet 126:195–214PubMedCrossRefGoogle Scholar
  36. 36.
    Piscopo P, Marcon G, Piras MR et al (2008) A novel PSEN2 mutation associated with a peculiar phenotype. Neurology 70:1549–1554PubMedCrossRefGoogle Scholar
  37. 37.
    Rossi G, Giaccone G, Maletta R et al (2004) A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology 63:910–912PubMedCrossRefGoogle Scholar
  38. 38.
    Rovelet-Lecrux A, Hannequin D, Raux G et al (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26PubMedCrossRefGoogle Scholar
  39. 39.
    Saito T, Suemoto T, Brouwers N et al (2011) Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci 14:1023–1032PubMedCrossRefGoogle Scholar
  40. 40.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMedGoogle Scholar
  41. 41.
    Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061PubMedCrossRefGoogle Scholar
  42. 42.
    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 14:837–842PubMedCrossRefGoogle Scholar
  43. 43.
    Shepherd C, McCann H, Halliday GM (2009) Variations in the neuropathology of familial Alzheimer’s disease. Acta Neuropathol 118:37–52PubMedCrossRefGoogle Scholar
  44. 44.
    Shimojo M, Sahara N, Mizoroki T et al (2008) Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in cell models and knock-in mouse brains: familial Alzheimer disease-linked mutation impairs gamma-site cleavage of amyloid precursor protein C-terminal fragment beta. J Biol Chem 283:16488–16496PubMedCrossRefGoogle Scholar
  45. 45.
    Suzuki N, Iwatsubo T, Odaka A, Ishibashi Y, Kitada C, Ihara Y (1994) High tissue content of soluble beta 1–40 is linked to cerebral amyloid angiopathy. Am J Pathol 145:452–460PubMedGoogle Scholar
  46. 46.
    Takami M, Nagashima Y, Sano Y et al (2009) gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 29:13042–13052PubMedCrossRefGoogle Scholar
  47. 47.
    Takao M, Ghetti B, Murrell JR et al (2001) Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures. J Neuropathol Exp Neurol 60:1137–1152PubMedGoogle Scholar
  48. 48.
    Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRefGoogle Scholar
  49. 49.
    Tomidokoro Y, Rostagno A, Neubert TA et al (2010) Iowa variant of familial Alzheimer’s disease: accumulation of posttranslationally modified AbetaD23N in parenchymal and cerebrovascular amyloid deposits. Am J Pathol 176:1841–1854PubMedCrossRefGoogle Scholar
  50. 50.
    Van Vickle GD, Esh CL, Kokjohn TA et al (2008) Presenilin-1 280Glu→Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer’s disease. Mol Med 14:184–194PubMedGoogle Scholar
  51. 51.
    Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539PubMedCrossRefGoogle Scholar
  52. 52.
    Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB (1997) Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem 272:22364–22372PubMedCrossRefGoogle Scholar
  53. 53.
    Weggen S, Eriksen JL, Das P et al (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414:212–216PubMedCrossRefGoogle Scholar
  54. 54.
    Welander H, Frånberg J, Graff C et al (2009) Abeta43 is more frequent than Abeta40 in amyloid plaque cores from Alzheimer disease brains. J Neurochem 110:697–706PubMedCrossRefGoogle Scholar
  55. 55.
    Welge V, Fiege O, Lewczuk P et al (2009) Combined CSF tau, p-tau181 and amyloid-beta 38/40/42 for diagnosing Alzheimer’s disease. J Neural Transm 116:203–212PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Maria Luisa Moro
    • 1
  • Giorgio Giaccone
    • 1
  • Raffaella Lombardi
    • 1
  • Antonio Indaco
    • 1
  • Andrea Uggetti
    • 1
  • Michela Morbin
    • 1
  • Stefania Saccucci
    • 1
  • Giuseppe Di Fede
    • 1
  • Marcella Catania
    • 1
  • Dominic M. Walsh
    • 2
  • Andrea Demarchi
    • 3
  • Annemieke Rozemuller
    • 4
  • Nenad Bogdanovic
    • 5
  • Orso Bugiani
    • 1
  • Bernardino Ghetti
    • 6
  • Fabrizio Tagliavini
    • 1
  1. 1.Fondazione IRCCS Istituto Neurologico Carlo Besta, MilanoMilanItaly
  2. 2.Laboratory for Neurodegenerative Research, Brigham and Women’s HospitalHarvard Institute of MedicineBostonUSA
  3. 3.ALS TO2, Ospedale Giovanni BoscoTurinItaly
  4. 4.Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  5. 5.Division of Clinical Geriatrics, Department for Neurobiology, Caring Sciences and SocietyKarolinska Institutet and Karolinska University HospitalStockholmSweden
  6. 6.Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease CenterIndiana University School of MedicineIndianapolisUSA

Personalised recommendations