Acta Neuropathologica

, 117:19 | Cite as

Cytoskeletal alterations differentiate presenilin-1 and sporadic Alzheimer’s disease

  • Adele Woodhouse
  • Claire E. Shepherd
  • Anna Sokolova
  • Victoria L. Carroll
  • Anna E. King
  • Glenda M. Halliday
  • Tracey C. DicksonEmail author
  • James C. Vickers
Original Paper


Most cases of Alzheimer’s disease (AD) are sporadic in nature, although rarer familial AD (FAD) cases have provided important insights into major pathological disease mechanisms. Mutations in the presenilin 1 gene (PS1) are responsible for the majority of FAD cases, causing an earlier age of onset and more rapid progression to end-stage disease than seen in sporadic AD. We have investigated the cytoskeletal alterations in neuritic AD pathology in a cohort of FAD cases in comparison to sporadic AD and pathologically aged cases. Tau-immunoreactive neurofibrillary tangle (NFT) loads were similar between PS1 FAD and sporadic AD cases. Similarly, plaque loads, both β-amyloid (Aβ) and thioflavine S, in PS1 FAD and sporadic AD cases were not significantly different; however, in pathologically aged cases, they were significantly lower than those in PS1 cases, but were not different from sporadic AD cases. The ‘cotton wool’ plaque characteristic of PS1 cases did not demonstrate a high density of dystrophic neurites compared to other Aβ plaque types, but did demonstrate a localised mass effect on the neuropil. Despite minimal differences in plaque and NFT loads, immunolabelling demonstrated clear phenotypic differences in the NFTs and dystrophic neurites in PS1 FAD cases. Presenilin-1 cases exhibited significantly (P < 0.05) more tau-positive NFTs that were immunolabelled by the antibody SMI312 (anti-phosphorylated NF protein and phosphorylated tau) than sporadic AD cases. Presenilin-1 cases also exhibited numerous ring-like NF-positive and elongated tau-labelled dystrophic neurites, whereas these dystrophic neurite types were only abundant at the very early (pathologically aged cases) or very late stages of sporadic AD progression, respectively. These differences in cytoskeletal pathology in PS1 cases suggest an accelerated rate of neuritic pathology development, potentially due to mutant PS1 influencing multiple pathogenic pathways.


Presenilin-1 Familial Alzheimer’s disease Dystrophic neurites Neurofibrillary tangles Cotton wool plaques 



Tissues were received from the Australian Brain Donor Programs Prince of Wales Medical Research Institute Tissue Resource Centre and South Australian Brain Bank, and from the Sun Health Research Institute in Arizona, USA. We wish to thank the study participants and their families who have given considerable time and eventually brain tissue to this research program, to those who participated in clinically evaluating study participants and to the staff of the neuropathology laboratory at POWMRI for tissue processing. Thanks also to Michelle Hill for her assistance with the Western Blots. This research was supported by the University of New South Wales, Gold Star Award, the Tasmanian Masonic Centenary Medical Research Foundation, National Health and Medical Research Council and the J.O. and J.R. Wicking Charitable Trust (ANZ Charitable Services). The Australian Brain Donor Programs Prince of Wales Medical Research Institute Tissue Resource Centre and South Australian Brain Bank are supported by the National Health and Medical Research Council of Australia. G.M.H. is a Principal Research Fellow and T.C.D. a Career Development Fellow of the National Health and Medical Research Council of Australia.


  1. 1.
    Akiyama H, Schwab C, Kondo H et al (2002) Morphologically distinct plaque types differentially affect dendritic structure and organization in the early and late stages of Alzheimer’s disease. Acta Neuropathol 103:377–383CrossRefGoogle Scholar
  2. 2.
    Armstrong RA (1998) β-Amyloid plaques: stages in life history or independent origin? Dement Geriatr Cogn Disord 9:227–238PubMedCrossRefGoogle Scholar
  3. 3.
    Biernat J, Wu Y-Z, Timm T et al (2002) Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol Biol Cell 13:4013–4028PubMedCrossRefGoogle Scholar
  4. 4.
    Blanchard V, Moussaoui S, Czech C et al (2003) Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/PS1 transgenic mice. Exp Neurol 184:247–263PubMedCrossRefGoogle Scholar
  5. 5.
    Borchelt DR, Thinakaran G, Eckman CB et al (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
  6. 6.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  7. 7.
    Busciglio J, Lorenzo A, Yeh J, Yanker BA (1995) β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–888PubMedCrossRefGoogle Scholar
  8. 8.
    Campion D, Dumanchin C, Hannequin D et al (1999) Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 65:664–670PubMedCrossRefGoogle Scholar
  9. 9.
    Chen Q, Nakajima A, Choi SH, Xiong X, Tang YP (2008) Loss of presenilin function causes Alzheimer’s disease-like neurodegeneration in the mouse. J Neurosci Res 86:1615–1626PubMedCrossRefGoogle Scholar
  10. 10.
    Crook R, Verkkoniemi A, Perez-Tur J et al (1998) A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to the deletion of exon 9 of presenilin 1. Nat Med 4:452–455PubMedCrossRefGoogle Scholar
  11. 11.
    Czech C, Tremp G, Pradier L (2000) Presenilins and Alzheimer’s disease: biological functions and pathogenic mechanisms. Prog Neurobiol 60:363–384PubMedCrossRefGoogle Scholar
  12. 12.
    De Felice FG, Wu D, Lambert MP et al (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers. Neurobiol Aging 29:1334–1347PubMedCrossRefGoogle Scholar
  13. 13.
    Dickson TC, Chuckowree JA, Chuah MI, West AK, Vickers JC (2005) Novel Alzheimer’s disease pathology reflects variable neuronal vulnerability and demonstrates the role of β-amyloid plaques in neurodegeneration. Neurobiol Dis 18:286–295PubMedCrossRefGoogle Scholar
  14. 14.
    Dickson TC, Vickers JC (2001) The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer’s disease. Neuroscience 105:99–107PubMedCrossRefGoogle Scholar
  15. 15.
    Dickson TC, King CE, McCormack GH, Vickers JC (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Exp Neurol 156:100–110PubMedCrossRefGoogle Scholar
  16. 16.
    Dowjat WK, Wisniewski H, Wisniewski T (2001) Alzheimer’s disease presenilin-1 expression modulates the assembly of neurofilaments. Neuroscience 103:1–8PubMedCrossRefGoogle Scholar
  17. 17.
    Evans J, Sumners C, Moore J et al (2002) Characterisation of mitotic neurons derived from adult rat hypothalamus and brain stem. J Neurophysiol 87:1076–1085PubMedGoogle Scholar
  18. 18.
    Ferreira A, Lu Q, Orecchio L, Kosik KS (1997) Selective phosphorylation of adult tau isoforms in mature hippocampal neurons exposed to fibrillar Abeta. Mol Cell Neurosci 9:220–234PubMedCrossRefGoogle Scholar
  19. 19.
    Fukumoto H, Asami-Odaka AS, Uzuki N, Iwatsubo T (1996) Association of Aβ40-positive senile plaques with microglial cells in the brains of patients with Alzheimer’s disease and in non-demented aged individuals. Neurodegeneration 5:13–17PubMedCrossRefGoogle Scholar
  20. 20.
    Giannakopoulos P, Herrmann FR, Bussiere T et al (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60:1495–1500PubMedGoogle Scholar
  21. 21.
    Gomez-Isla T, Growdon WB, McNamara MJ et al (1999) The impact of different presenilin 1 and presenilin 2 mutation on amyloid deposition neurofibrillary changes and neuronal loss in familial Alzheimer’s disease brain: evidence for other phenotype-modifying factors. Brain 122:1709–1719PubMedCrossRefGoogle Scholar
  22. 22.
    Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M (1998) Genetic dissection of Alzheimer’s disease and related dementias: amyloid and its relationship to tau. Nat Neurosci 1:355–358PubMedCrossRefGoogle Scholar
  23. 23.
    Houlden H, Baker M, McGowan E et al (2000) Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol 48:806–808PubMedCrossRefGoogle Scholar
  24. 24.
    Ishihara T, Higuchi M, Zhang B et al (2001) Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J Neurosci 21:6026–6035PubMedGoogle Scholar
  25. 25.
    Ishii K, Ii K, Hasegawa T, Shoji S, Doi A, Mori H (1997) Increased Abeta 42(43)-plaque deposition in early-onset familial Alzheimer’s disease brains with the deletion of exon 9 and the missense point mutation (H163R) in the PS-1 gene. Neurosci Lett 228:17–20PubMedCrossRefGoogle Scholar
  26. 26.
    Karlstrom H, Brooks WS, Kwok JBJ et al (2008) Variable phenotype of Alzheimer’s disease with spastic paraparesis. J Neurochem 104:573–583PubMedGoogle Scholar
  27. 27.
    Kwok JBJ, Halliday GM, Brooks WS et al (2003) Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer’s disease with non-cored plaques and no neuritic dystrophy. J Biol Chem 278:6748–6754PubMedCrossRefGoogle Scholar
  28. 28.
    Lazarov O, Morfini GA, Pigino G et al (2007) Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer’s Disease-linked mutant presenilin 1. J Neurosci 27:7011–7020PubMedCrossRefGoogle Scholar
  29. 29.
    Lippa CF, Saunders AM, Smith TW et al (1996) Familial and sporadic Alzheimer’s disease: neuropathology cannot exclude a final common pathway. Neurology 46:406–412PubMedGoogle Scholar
  30. 30.
    Mann DMA, Pickering-Brown SM, Takeuchi A, Iwatsubo T, Familial Alzheimer’s disease pathology study group (2001) Amyloid angiopathy and variability in amyloid-β deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol 158:2165–2175PubMedGoogle Scholar
  31. 31.
    Mann DMA, Takeuchi A, Sato S et al (2001) Cases of Alzheimer’s disease due to deletion of exon 9 of the presenilin-1 gene show an unusual but characteristic β-amyloid pathology known as ‘cotton wool’ plaques. Neuropathol Appl Neurobiol 27:189–196PubMedCrossRefGoogle Scholar
  32. 32.
    Masliah E, Mallory M, Hansen L, Alford M, DeTeresa R, Terry R (1993) An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer’s disease. Am J Pathol 142:871–881PubMedGoogle Scholar
  33. 33.
    Masliah E, Sisk A, Mallory M, Games D (2001) Neurofibrillary pathology in transgenic mice overexpressing V717F β-Amyloid precursor protein. J Neuropathol Exp Neurol 60:357–368PubMedGoogle Scholar
  34. 34.
    Meyer-Luehmann M, Spires-Jones TL, Prada C et al (2008) Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724PubMedCrossRefGoogle Scholar
  35. 35.
    Mirra SS, Heyman A, McKeel D et al (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathological assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  36. 36.
    Pérez M, Asunción Morán M, Ferrer I et al (2008) Phosphorylated tau in neuritic plaques of APPsw/Tauvlw transgenic mice and Alzheimer disease. Acta Neuropathol 116:409–418PubMedCrossRefGoogle Scholar
  37. 37.
    Pigino G, Pelsman A, Mori H, Busciglio J (2001) Presenilin-1 mutations reduce cytoskeletal association, deregulate neurite growth, and potentiate neuronal dystrophy and tau phosphorylation. J Neurosci 21:834–842PubMedGoogle Scholar
  38. 38.
    Porzig R, Singer D, Hoffmann R (2007) Epitope mapping of mABs AT8 and Tau5 directed against hyperphosphoylated regions of the human tau protein. Biochem Biophys Res Commun 358:644–649PubMedCrossRefGoogle Scholar
  39. 39.
    Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368PubMedCrossRefGoogle Scholar
  40. 40.
    Savage MJ, Iqbal M, Loh T et al (1994) Cathespin G: localization in human cerebral cortex and generation of amyloidogenic fragments from the beta-amyloid precursor protein. Neuroscience 60:607–619PubMedCrossRefGoogle Scholar
  41. 41.
    Scheuner D, Eckman C, Jensen M et al (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 2:850–852CrossRefGoogle Scholar
  42. 42.
    Schmidt M, Lee VM, Trojanowski JQ (1989) Analysis of epitopes shared by Hirano bodies and neurofilament proteins in normal and Alzheimer’s disease hippocampus. Lab Invest 60:513–522PubMedGoogle Scholar
  43. 43.
    Selkoe DJ (1996) (1996) Amyloid beta-protein and the genetics of Alzheimer’s disease. J Biol Chem 271:18295–18298PubMedGoogle Scholar
  44. 44.
    Shepherd CE, Gregory GC, Vickers JC et al (2004) Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques. Neurobiol Dis 15:115–119PubMedCrossRefGoogle Scholar
  45. 45.
    Stanford PM, Shepherd CE, Halliday GM et al (2003) Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia. Brain 126:814–826PubMedCrossRefGoogle Scholar
  46. 46.
    Steiner H, Revesz T, Neumann M et al (2001) A pathogenic presenilin-1 deletion causes aberrant Aβ42 production in the absence of congophilic amyloid plaques. J Biol Chem 276:7233–7239PubMedCrossRefGoogle Scholar
  47. 47.
    Su JH, Cummings BJ, Cotman CW (1996) Plaque biogenesis in brain aging and Alzheimer’s disease. I. Progressive changes in phosphorylation states of paired helical filaments and neurofilaments. Brain Res 739:79–87PubMedCrossRefGoogle Scholar
  48. 48.
    Su JH, Cummings BJ, Cotman CW (1998) Plaque biogenesis in brain aging and Alzheimer’s disease. II. Progressive transformation and developmental sequence of dystrophic neurites. Acta Neuropathol 96:463–471PubMedCrossRefGoogle Scholar
  49. 49.
    Takao M, Ghetti B, Hayakawa I et al (2002) A novel mutation (G217D) in the presenilin 1 gene (PSEN1) in a Japanese family: presenile dementia and Parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol 104:155–170PubMedCrossRefGoogle Scholar
  50. 50.
    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 USA 95:9637–9641PubMedCrossRefGoogle Scholar
  51. 51.
    Vickers JC, Dickson TC, Adlard PA, Saunders HL, King CE, McCormack G (2000) The cause of neuronal degeneration in Alzheimer’s disease. Prog Neurobiol 60:139–165PubMedCrossRefGoogle Scholar
  52. 52.
    Vickers JC, Riederer BM, Marugg R, Buée-Scherrer V, Buée L, Delacourtes A (1994) Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer’s disease. Neuroscience 62:1–13PubMedCrossRefGoogle Scholar
  53. 53.
    Woodhouse A, West AK, Chuckowree JA, Vickers JC, Dickson TC (2005) Does β-amyloid plaque formation cause structural injury to neuronal processes? Neurotox Res 7:5–15PubMedCrossRefGoogle Scholar
  54. 54.
    Woodhouse A, Vickers JC, Adlard PA, Dickson TC (2007) Dystrophic neurites in TgCRND8 and Tg2576 mice mimic human pathological brain aging. Neurobiol Aging (in press). 18 October 2007 [Epub ahead of print]Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Adele Woodhouse
    • 1
  • Claire E. Shepherd
    • 2
    • 3
  • Anna Sokolova
    • 1
  • Victoria L. Carroll
    • 1
  • Anna E. King
    • 1
  • Glenda M. Halliday
    • 2
    • 3
  • Tracey C. Dickson
    • 1
    Email author
  • James C. Vickers
    • 1
  1. 1.Wicking Dementia Research and Education Centre and NeuroRepair GroupMenzies Research InstituteHobartAustralia
  2. 2.Prince of Wales Medical Research InstituteSydneyAustralia
  3. 3.University of New South WalesSydneyAustralia

Personalised recommendations