Elsevier

Brain Research

Volume 840, Issues 1–2, 4 September 1999, Pages 125-137
Brain Research

Research report
Learning abilities, NGF and BDNF brain levels in two lines of TNF-α transgenic mice, one characterized by neurological disorders, the other phenotypically normal

https://doi.org/10.1016/S0006-8993(99)01748-5Get rights and content

Abstract

In this study we used two lines of transgenic mice overexpressing tumor necrosis factor alpha (TNF-α) in the central nervous system (CNS), one characterized by reactive gliosis, inflammatory demyelination and neurological deficits (Tg6074) the other showing no neurological or phenotypical alterations (TgK3) to investigate the effect of TNF-α on brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels and learning abilities. The results showed that the amount of NGF in the brain of Tg6074 and TgK3 transgenic mice is low in the hippocampus and in the spinal cord, increases in the hypothalamus of Tg6074 and showed no significant changes in the cortex. BDNF levels were low in the hippocampus and spinal cord of TgK3. BDNF increased in the hypothalamus of TgK3 and Tg6074 while in the cortex, BDNF increased only in Tg6074 mice. Transgenic mice also had memory impairments as revealed by the Morris Water Maze test. These findings indicate that TNF-α significantly influences BDNF and NGF synthesis, most probably in a dose-dependent manner. Learning abilities were also differently affected by overexpression of TNF-α, but were not associated with inflammatory activity. The possible functional implications of our findings are discussed.

Introduction

Tumor necrosis factor alpha (TNF-α) and nerve growth factor (NGF) are both involved in a variety of biological activities 27, 35, 42, 44, 46. For example, NGF is a neurotrophin and a neuroimmune signaling molecule involved in the development and survival of numerous neurons of the peripheral and central nervous system (CNS), and in cognitive processes 21, 47. NGF is also known to exert biological activities on non-neuronal cell, since it enhances B and T lymphocyte growth and differentiation 26, 36, causes mast cells proliferation and degranulation 3, 12, 37, accelerates wound healing [28], and influences memory B cell activity [48]. Moreover, NGF synthesis and distribution are affected during neuroimmunological and inflammatory insults 5, 6, 7.

TNF-α is a major immunomodulatory molecule produced by cells of the immune and the nervous systems. It is particularly expressed during immune, inflammatory but also in certain neurodegenerative disorders 29, 50. The functional role of TNF-α on the nervous system is a matter of controversy, since there is evidence indicating deleterious and protective effects of TNF-α during and/or after neuronal damages 14, 17, 19, 41. The hypothesis of a protective role in the nervous system is supported by the evidence that TNF-α protects postmitotic cells, including neurons exposed to metabolic, excitotoxic and oxidative insults 15, 31, 32, and that knockout mice lacking TNF-α receptors seem to be particularly vulnerable to brain injury [11].

Since TNF-α promotes NGF synthesis 22, 23, 24, an important question raised by these latter observations is whether the effect of TNF-α on NGF synthesis is dependent or independent of the inflammatory conditions of the tissues. To address this question we have used transgenic mice expressing high levels of brain TNF-α. Probert et al. 2, 38, 40have recently developed several lines of TNF-α transgenic mice which may help to elucidate whether the effect of TNF-α is mediated by the stimulation of biological mediators, including NGF. Two lines of these mice are Tg6074 and TgK3. Tg6074 mice express a murine TNF-α transgene by glial precursor cells [2]and display several neuropathological characteristics, notably inflammatory demyelination and neurological abnormalities. TgK3 mice express an uncleavable mutant of human TNF-α in neurons and do not show any neurological or phenotypic alterations. We have previously shown that the cell source of TNF-α expression is important for determining the outcome of TNF-α effects. For example, astrocyte-specific but not neuron-specific expression of transmembrane TNF-α can trigger CNS inflammation, demyelination and the development of multiple sclerosis-type plaques 1, 2. Whether this diverse manifestation of brain TNF-α expression differentially affects brain NGF is, however, unknown. Using Tg6074 mice [40], we have previously reported that TNF-α influences the distribution of NGF levels in several brain regions [4]. Whether this NGF alteration was linked to the widespread brain neuroinflammatory condition or to a direct exposure to TNF-α was not established. This study was therefore aimed to investigate whether the action of TNF-α on NGF synthesis and learning abilities is the indirect consequence of its pro-inflammatory effect or a direct result of the presence of TNF-α. A second aim was to investigate whether brain TNF-α influences also the constitutive level of brain-derived neurotrophic factor (BDNF), a neurotrophin of the NGF family widely distributed in the CNS.

Section snippets

Transgenic mouse models

In this study we have used Tg6074 and TgK3 transgenic mice both generated at the Hellenic Pasteur Institute 1, 2, 38, 39, 40. Tg6074 mice express a modified 3″ untranslated murine TNF-α-globin gene construct, under the control of the murine TNF-α promoter, specifically in the CNS, and that spontaneously develop inflammatory demyelinating CNS disease with 100% phenotypic penetrance from around 3–8 weeks of age. The transgene copy number in heterozygous Tg6074 progeny was estimated to be >100

Morphogenetic observations

No significant differences in body weight were observed during the first 20 days of postnatal life between both lines of transgenic mice and their respective controls. After this age Tg6074 mice gained weight more slowly than their respective wild type mice and displayed differences in morphogenetic aspects such as hair growth, tooth eruption and eyelid opening 20, 40. TgK3 mice did not show developmental delays as compared to their respective controls, and did not display any neurological or

The two lines of transgenic mice

The present study was undertaken to investigate whether and to what extent overexpression of TNF-α in the brain of transgenic mice affects the constitutive levels of NGF and BDNF in the CNS and learning performances. To carry out these studies we have used two lines of these mice, one (Tg6074) characterized by a low increase in body weight after puberty, a reduced life span, neurological and neuroinflammatory deficits, and the other phenotypically normal (TgK3).

Learning ability changes and brain TNF-α presence

Both TgK3 and Tg6074 displayed

Conclusions

A relevant question raised by our observations is whether TNF-α exerts its action on cells that are able to produce both NGF and BDNF or on separate cell types. The present study clearly indicates that an appropriate dose of brain TNF-α can promote NGF synthesis in the absence of gliosis and inflammatory responses and points to a possible potential physiological role of TNF-α in the modulation of NGF on NGF-dependent cells and in neuropathologies associated with NGF and BDNF deficits. Our

Acknowledgements

This study was supported by the European Union Biotech Project (BIO4-CT96-0174). We thank Dr. Flavia Chiarotti for the statistical suggestions.

References (53)

  • L.J. Eddy et al.

    Tumor necrosis factor-α pretreatment is protective in a rat model of myocardial ischemia-reperfusion injury

    Biochem. Biophys. Res. Commun.

    (1992)
  • M. Fiore et al.

    Neurobehavioral alterations in developing transgenic mice expressing TNF-α in the brain

    Brain Behav. Immun.

    (1996)
  • R.A. Gadient et al.

    Interleukin-1β and tumor necrosis factor-α synergistically stimulate nerve growth factor (NGF) release from cultured rat astrocytes

    Neurosci. Lett.

    (1990)
  • A. Hattori et al.

    Tumor necrosis factor is marked synergistic with IL-β and Interferon-γ in stimulating the production of NGF in fibroblast

    FEBS Lett.

    (1994)
  • A. Hattori et al.

    Tumor necrosis factor stimulates the synthesis and secretion of biologically active nerve growth factor in non-neuronal cells

    J. Biol. Chem.

    (1993)
  • A. Lambiase et al.

    Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors

    J. Allergy Clin. Immunol.

    (1997)
  • J.E. Merrill et al.

    Cytokines in inflammatory brain lesions: helpful and harmful

    Trends Neurosci.

    (1996)
  • R. Morris

    Developments of a water-maze procedure for studying spatial learning in the rat

    J. Neurosci. Methods

    (1984)
  • L. Probert et al.

    TNF-alpha transgenic and knockout models of CNS inflammation and degeneration

    J. Neuroimmunol.

    (1997)
  • L. Probert et al.

    TNF and related molecules: trends in neuroscience and clinical applications

    J. Neuroimmunol.

    (1997)
  • S.Y. Tam et al.

    Expression of functional TrkA receptor tyrosine kinase in the HMC-1 human mast cell line and in human mast cells

    Blood

    (1997)
  • M. Torcia et al.

    Nerve growth factor is an autocrine survival factor for memory B lymphocytes

    Cell

    (1996)
  • J. Vilcek et al.

    Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions

    J. Biol. Chem.

    (1991)
  • K. Akassoglou et al.

    Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice

    J. Immunol.

    (1997)
  • L. Aloe et al.

    Nerve growth factor and autoimmune diseases

    Autoimmunity

    (1994)
  • M. Bianchi et al.

    Cytokines and cognitive function in mice

    Biol. Signals Recept.

    (1998)
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      TNF-α concentrations are found elevated in various neuropathological states that are related to learning and memory deficits, highlighting a possible role in plasticity [44]. For this purpose, much work has been carried out in the hippocampus; in fact, animal studies provide evidence that mice over-expressing TNF-α demonstrate memory impairments and disrupted learning capabilities [45,46], supporting the notion that TNF-α activity at the hippocampus and the synaptic level may influence brain function and behavior [47,48]. Consistently, a negative effect of TNF-α was found following intra-hippocampal administration to rats, which lead to impaired hippocampal-dependent working memory, as shown by an increased number of errors and longer latencies regarding the runway task [49].

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    Current address: Department of Pharmacology, State University of New York, Stony Brook, NY 11794-8651, USA.

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