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Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer’s disease

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Abstract

Perineuronal matrix is an extracellular protein scaffold to shape neuronal responsiveness and survival. Whilst perineuronal nets engulf the somatodendritic axis of neurons, axonal coats are focal extracellular protein aggregates surrounding individual synapses. Here, we addressed the chemical identity and subcellular localization of both perineuronal and perisynaptic matrices in the human hippocampus, whose neuronal circuitry is progressively compromised in Alzheimer’s disease. We hypothesized that (1) the cellular expression sites of chondroitin sulphate proteoglycan-containing extracellular matrix associate with specific neuronal identities, reflecting network dynamics, and (2) the regional distribution and molecular composition of axonal coats must withstand Alzheimer’s disease-related modifications to protect functional synapses. We show by epitope-specific antibodies that the perineuronal protomap of the human hippocampus is distinct from other mammals since pyramidal cells but not calretinin+ and calbindin+ interneurons, neurochemically classified as novel neuronal subtypes, lack perineuronal nets. We find that cartilage link protein-1 and brevican-containing matrices form isolated perisynaptic coats, engulfing both inhibitory and excitatory terminals in the dentate gyrus and entorhinal cortex. Ultrastructural analysis revealed that presynaptic neurons contribute components of perisynaptic coats via axonal transport. We demonstrate, by combining biochemical profiling and neuroanatomy in Alzheimer’s patients and transgenic (APdE9) mice, the preserved turnover and distribution of axonal coats around functional synapses along dendrite segments containing hyperphosphorylated tau and in amyloid-β-laden hippocampal microdomains. We conclude that the presynapse-driven formation of axonal coats is a candidate mechanism to maintain synapse integrity under neurodegenerative conditions.

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Acknowledgments

The authors thank G. Brückner and R. Matthews for comments and antibodies, and T. Hortobágyi (London Neurodegenerative Diseases Brain Bank, United Kingdom) for post-mortem human hippocampal tissues used in biochemical assays. This work was supported by the Scottish Universities Life Science Alliance (T.H., A.A.), the German Research Foundation GRK 1097 “INTERNEURO” (T.A.; M.M), the EU-Project “Neuropro” (Grant Agreement No. 223077), the COST Action BM1001 “Brain Extracellular Matrix in Health and Disease”, the Alzheimer Forschungsinitiative e.V. (AFI#11861, M.M.), the German Research Foundation (Grant MO 2249/2-1, M.M.) within the PP 1608, the Dunhill Medical Trust (R173/1110; J.A.), the Swedish Research Council (T.H.) and the European Union FP7 MEMOLOAD grant (HEALTH-F2-2007-201159, H.T. and T.H.).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary

    Dávid Lendvai, Georgina Gáti, Gábor Baksa & Alán Alpár

  2. Paul Flechsig Institute for Brain Research, Faculty of Medicine, Universität Leipzig, Leipzig, Germany

    Markus Morawski, Carsten Jäger & Thomas Arendt

  3. Department of Neuroscience and Physiology, SUNY Upstate Medical University, WH 3240, 750 East Adams Street, Syracuse, NY, 13210, USA

    Markus Morawski

  4. Department of Theory, Wigner Research Centre for Physics, Institute for Particle and Nuclear Physics, Hungarian Academy of Sciences, Budapest, Hungary

    László Négyessy

  5. Second Department of Pathology, Semmelweis University, Budapest, Hungary

    Tibor Glasz

  6. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

    Johannes Attems

  7. A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland

    Heikki Tanila

  8. Department of Neurology, Kuopio University Hospital, Kuopio, Finland

    Heikki Tanila

  9. European Neuroscience Institute, University of Aberdeen, Aberdeen, AB25 2ZD, UK

    Tibor Harkany & Alán Alpár

  10. Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Tibor Harkany & Alán Alpár

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  1. Dávid Lendvai
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  2. Markus Morawski
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  9. Heikki Tanila
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  10. Thomas Arendt
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Correspondence to Thomas Arendt or Alán Alpár.

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D. Lendvai and M. Morawski contributed equally to the present study.

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Lendvai, D., Morawski, M., Négyessy, L. et al. Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer’s disease. Acta Neuropathol 125, 215–229 (2013). https://doi.org/10.1007/s00401-012-1042-0

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