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Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer’s disease neuropathology

  • Alzheimer's Disease and Related Disorders - Original Article
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Abstract

The uridine nucleotide-activated P2Y2, P2Y4 and P2Y6 receptors are widely expressed in the brain and are involved in many CNS processes, including those which malfunction in Alzheimer’s disease (AD). However, the status of these receptors in the AD neocortex, as well as their putative roles in the pathogenesis of neuritic plaques and neurofibrillary tangles, remain unclear. In this study, we used immunoblotting to measure P2Y2, P2Y4 and P2Y6 receptors in two regions of the postmortem neocortex of neuropathologically assessed AD patients and aged controls. P2Y2 immunoreactivity was found to be selectively reduced in the AD parietal cortex, while P2Y4 and P2Y6 levels were unchanged. In contrast, all three receptors were preserved in the occipital cortex, which is known to be minimally affected by AD neuropathology. Furthermore, reductions in parietal P2Y2 immunoreactivity correlated both with neuropathologic scores and markers of synapse loss. These results provide a basis for considering P2Y2 receptor changes as a neurochemical substrate of AD, and point towards uridine nucleotide-activated P2Y receptors as novel targets for disease-modifying AD pharmacotherapeutic strategies.

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Acknowledgments

This study is supported by the Wellcome Trust, UK. We thank Dr. Brendan McDonald for the collection and classification of the postmortem samples. S. Kirvell is the Edmond J. Safra Fellow at Wolfson CARD, King’s College London. In Singapore, the work was supported by the National Medical Research Council (NMRC/0932/2005) to M. K. P. Lai and a Faculty Start-up grant to C. P. Chen. M. K. P. Lai would like to thank Olivia H. J. Oon for valuable assistance.

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Authors and Affiliations

  1. Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore

    Mitchell K. P. Lai & Michelle G. K. Tan

  2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore, 117597, Singapore

    Mitchell K. P. Lai, Jasinda Lee & Christopher P. Chen

  3. Wolfson Centre for Age-Related Diseases, King’s College London, London, SE1 1UL, UK

    Sara Kirvell, Carl Hobbs & Paul T. Francis

  4. Department of Neuropathology, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK

    Margaret M. Esiri

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  1. Mitchell K. P. Lai
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  2. Michelle G. K. Tan
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  3. Sara Kirvell
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  4. Carl Hobbs
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Correspondence to Mitchell K. P. Lai.

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Lai, M.K.P., Tan, M.G.K., Kirvell, S. et al. Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer’s disease neuropathology. J Neural Transm 115, 1165–1172 (2008). https://doi.org/10.1007/s00702-008-0067-y

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  • DOI: https://doi.org/10.1007/s00702-008-0067-y

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