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Granular expression of prolyl-peptidyl isomerase PIN1 is a constant and specific feature of Alzheimer’s disease pathology and is independent of tau, Aβ and TDP-43 pathology

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Abstract

Alzheimer’s disease (AD) manifests with progressive memory loss and decline of spatial awareness and motor skills. Neurofibrillary tangles (NFTs) represent one of the pathological hallmarks of AD. Previous studies suggest that the enzyme prolyl-peptidyl cis–trans isomerase PIN1 [protein interacting with NIMA (never in mitosis A)-1] recognizes hyperphosphorylated tau (in NFTs) and facilitates its dephosphorylation, thereby recovering its function. This study aims to determine the frequency, severity and distribution of PIN1 immunoreactivity and its relationship to NFTs and other neuropathological markers of neurodegeneration such as amyloid-β (Aβ) plaques and transcription-responsive DNA-binding protein of M r 43 kDa (TDP-43). Immunohistochemical analysis of 194 patients (46 with AD, 43 with Parkinson’s disease/dementia with Lewy bodies, 12 with progressive supranuclear palsy/corticobasal degeneration, 36 with frontotemporal lobar degeneration, 21 with motor neuron disease and 34 non-demented (ND) individuals) revealed an increased frequency and severity of PIN1 immunoreactive inclusions in AD as compared to all diagnostic groups (P < 0.001). The hippocampal and cortical distribution of PIN1 granules was distinct from that of NFTs, Aβ and TDP-43 pathologies, though the frequency of neurons with PIN1 immunoreactivity increased with increasing NFT pathology. There was a progressive increase in PIN1 changes in ND individuals as the degree of AD-type pathological changes increased. Present findings indicate that PIN1 changes are a constant feature of AD pathology and could serve as a biomarker of the onset or spread of AD neuropathology independent of tau or Aβ.

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Acknowledgments

We wish to thank the Academic Cultural Office of Kuwait, London, and the Ministry of Higher Education, Kuwait, who kindly provided grant support for this work. We thank The UK Parkinson’s Disease Society Tissue Bank, the Thomas Willis Brain Bank, Oxford and Dr Eileen H Bigio (Northwestern Alzheimer Disease Center, AG13854, Northwestern University, Chicago, USA) who kindly provided some of the tissue samples employed in this study. We acknowledge the Alzheimer’s Research Trust and Alzheimer’s Society through the Brains for Dementia Research Initiative for supporting the work of the Manchester and Oxford Brain Banks. MME received financial support from the National Institute for Health Research (NIHR) via the Oxford Biomedical Research Centre.

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Authors and Affiliations

  1. Mental Health and Neurodegeneration Research Group, School of Community Based Medicine, Faculty of Medical and Human Sciences, Hope Hospital, Greater Manchester Neurosciences Centre, University of Manchester, Stott Lane, Salford, M6 8HD, UK

    Ayoub Dakson, Osamu Yokota, Michael Horan, Neil Pendleton, Anna Richardson, David Neary, Julie S. Snowden, Andrew Robinson, Yvonne S. Davidson & David M. A. Mann

  2. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Osamu Yokota

  3. Neuropathology Department, Level 1 West Wing, John Radcliffe Infirmary, University of Oxford, Oxford, OX3 9DU, UK

    Margaret Esiri

  4. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60619, USA

    Eileen H. Bigio

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  1. Ayoub Dakson
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  2. Osamu Yokota
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Correspondence to David M. A. Mann.

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Dakson, A., Yokota, O., Esiri, M. et al. Granular expression of prolyl-peptidyl isomerase PIN1 is a constant and specific feature of Alzheimer’s disease pathology and is independent of tau, Aβ and TDP-43 pathology. Acta Neuropathol 121, 635–649 (2011). https://doi.org/10.1007/s00401-011-0798-y

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  • DOI: https://doi.org/10.1007/s00401-011-0798-y

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