Elsevier

Experimental Neurology

Volume 188, Issue 2, August 2004, Pages 309-315
Experimental Neurology

Perineuronal nets potentially protect against oxidative stress

https://doi.org/10.1016/j.expneurol.2004.04.017Get rights and content

Abstract

A specialized form of extracellular matrix (ECM) termed perineuronal nets (PNs) consisting of large aggregating chondroitin sulfate proteoglycans (CSPGs), with hyaluronan and tenascin as main components, surrounds subpopulations of neurons. The glycosaminoglycan components of perineuronal nets form highly charged structures in the direct microenvironment of neurons and thus might be involved in local ion homeostasis. The polyanionic character suggests that perineuronal nets also potentially contribute to reduce the local oxidative potential in the neuronal microenvironment by scavenging and binding redox-active iron, thus providing some neuroprotection to net-associated neurons. Here, we show that neurons ensheathed by a perineuronal net in the human cerebral cortex are less frequently affected by lipofuscin accumulation than neurons without a net both in normal-aged brain and Alzheimer's disease (AD). As lipofuscin is an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalyzed oxidative processes, the present results suggest a neuroprotective function of perineuronal nets against oxidative stress, potentially involved in neurodegeneration.

Introduction

Perineuronal nets (PNs) are lattice-like aggregations of extracellular matrix (ECM) components, originally described by Golgi (1893) and Ramón Y Cajal (1987) as a reticular structure covering cell bodies and proximal dendrites of certain neurons. PNs are associated with different types of neurons in the brain of many vertebrates including man Celio and Blümcke, 1994, Celio et al., 1998, Oohira et al., 1994, Seeger et al., 1994, Wegner et al., 2003. PNs consist primarily of aggregating CSPGs complexed with hyaluronan and tenascin Brückner et al., 1998, Brückner et al., 2003, Köppe et al., 1997, Yamaguchi, 2000.

In the human cerebral cortex, PNs surround several types of interneurons as well as subpopulations of pyramidal cells, which are most frequently found in motor and primary sensory cortical areas Bertolotto et al., 1991, Hausen et al., 1996.

There are noticeable differences between the PNs of nonpyramidal cells and pyramidal cells as well as within the pyramidal cell group with respect to the molecular structure of the glycosaminoglycan chains of the chondroitin sulfate proteoglycans (CSPGs) Matthews et al., 2002, Ojima et al., 1998. Pyramidal cells, furthermore, always show a more delicate perineuronal CSPG immunoreactivity indicating a less intense abundance of proteoglycans compared to different types of nonpyramidal neurons ensheathed by a PN Hausen et al., 1996, Wegner et al., 2003.

The biological significance of PNs is not entirely clear, and several functions have been proposed. Through the inhibitory potential to cell adhesion and the repulsive properties of their molecular components against approaching axons and dendrites PNs might contribute to the stabilization of the ensheathed synaptic contacts, thereby reducing their neuroplastic potential Berardi et al., 2003, Pizzorusso et al., 2002, Rhodes and Fawcett, 2004. Perineuronal nets might thus be critically involved in the regulation of synaptic plasticity during maturation and in the adult (Hockfield et al., 1990; for a review, see Dityatev and Schachner, 2003). Other functions of PNs might be related to the polyanionic character. The glycosaminoglycan chains of PNs provide highly charged structures in the direct microenvironment of neurons that might be involved in local ion homeostasis. They can thus potentially act as buffering system for physiologically relevant ions such as calcium, potassium, and sodium around highly active types of neurons Brückner et al., 1993, Brückner et al., 1996, Härtig et al., 1999. These polyanionic components, however, might also interact with ions involved in generating oxidative stress such as iron. Through scavenging and binding of redox-active iron, PNs might be able to neutralize or reduce the potentially deleterious local oxidative potential in the neuronal microenvironment, thereby protecting neurons ensheathed by PNs against sequelae of oxidative damage. In a previous study, we could show that in Alzheimer's disease (AD), cortical areas highly enriched in PNs are less severely affected by neurofibrillary degeneration, and net-associated neurons are devoid of tangles (Brückner et al., 1999). In the present study, we intend to further specify these potential neuroprotective effects of PNs. As a hallmark for oxidative stress, we used the accumulation of lipofuscin, an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalyzed oxidative processes Porta, 2002, Sohal and Brunk, 1989, Tappel, 1973. We analyzed whether net-associated neurons are affected by accumulation of lipofuscin to the same extent or less frequently than neurons without PN in both normal aging brain and AD.

Section snippets

Cases and tissue preparation

Brains from three controls (mean age ± SEM, 73 ± 8.9 years) and five patients with AD (88 ± 1.25 years) were obtained at autopsy (Brain Bank of the University of Leipzig). Each AD case met the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA) criteria for definite diagnosis of Alzheimer's disease (McKhann et al., 1984). Neuropathological diagnosis was based on the NIA-Reagan Institute Criteria for

Results

Typical examples of net-associated neurons and their lipofuscin load are displayed in Fig. 1, Fig. 2. As apparent from the figures, intensely stained CSPG-immunoreactive PNs ensheath nonpyramidal cells. Pyramidal cells, on the contrary, are either devoid of PNs or decorated by a very delicate net that surrounds mainly cell bodies and proximal parts of apical dendrites. Lipofuscin accumulation is most prominent in neurons without PN. To some extent, clear lipofuscin deposits can also be detected

Discussion

The phenomenon of region-specific and cell type-selective neuronal vulnerability is a hallmark of neurodegenerative disorders including AD and provides the basis for currently used neuropathological staging Arendt, 2001, Braak et al., 2000, Hof et al., 1995, Morrison and Hof, 1997. While the entorhinal and transentorhinal cortices are affected in AD most constantly, primary motor and sensory cortices are much less vulnerable against neurofibrillary degeneration. The molecular basis for this

Acknowledgements

The authors wish to thank Mrs. Margit Schmidt and Mrs. Hildegard Gruschka for their excellent technical assistance. This study was supported by the Deutsche Forschungsgemeinschaft (grant AR 200/6-1), by the Deutsches Bundesministerium für Bildung, Forschung und Technologie (BMBF NBL3/01ZZ 0106), the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Leipzig at the Faculty of Medicine of the University of Leipzig (C1), and the European Commission (QLK6-CT-1999-02112).

References (50)

  • J.A. Joseph et al.

    Muscarinic receptor subtype determines vulnerability to oxidative stress in COS-7 cells

    Free Radic. Biol. Med

    (2002)
  • H. Ojima et al.

    Molecular heterogeneity of Vicia villosa-recognized perineuronal nets surrounding pyramidal and nonpyramidal neurons in the guinea pig cerebral cortex

    Brain Res

    (1998)
  • A. Oohira et al.

    Brain development and multiple molecular species of proteoglycan

    Neurosci. Res

    (1994)
  • T. Reinert et al.

    Quantitative microanalysis of perineuronal nets in brain tissue

    Nucl. Instrum. Methods B

    (2003)
  • G. Seeger et al.

    Mapping of perineuronal nets in the rat brain stained by colloidal iron hydroxide histochemistry and lectin cytochemistry

    Neuroscience

    (1994)
  • F. Wegner et al.

    Diffuse perineuronal nets and modified pyramidal cells immunoreactive for glutamate and the GABAA receptor α1 subunit from a unique entity in rat cerebral cortex

    Exp. Neurol

    (2003)
  • C. Bergeron et al.

    Copper/zinc superoxide dismutase expression in the human central nervous system. Correlation with selective neuronal vulnerability

    Am. J. Pathol

    (1996)
  • A. Bertolotto et al.

    Chondroitin sulfate proteoglycan surrounds a subset of human and rat CNS neurons

    J. Neurosci. Res

    (1991)
  • J.W. Boellaard et al.

    Ultrastructural heterogeneity of neuronal lipofuscin in the normal human cerebral cortex

    Acta Neuropathol. (Berl)

    (1986)
  • H. Braak et al.

    Neuropathological staging of Alzheimer-related changes

    Acta Neuropathol. (Berl)

    (1991)
  • H. Braak et al.

    Vulnerability of select neuronal types to Alzheimer's disease

    Ann. N. Y. Acad. Sci

    (2000)
  • K. Brodmann

    Vergleichende Lokalisationslehre der Großhirnrinde

    (1909)
  • G. Brückner et al.

    Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain

    Glia

    (1993)
  • G. Brückner et al.

    Extracellular matrix organization in various regions of rat brain grey matter

    J. Neurocytol

    (1996)
  • G. Brückner et al.

    Acute and long-lasting changes in extracellular-matrix chondroitin-sulphate proteoglycans induced by injection of chondroitinase ABC in the adult rat brain

    Exp. Brain Res

    (1998)
  • Cited by (0)

    View full text