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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

Abstract

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.

Keywords

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

Notes

Acknowledgments

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.

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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

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