Elsevier

Brain Research Bulletin

Volume 61, Issue 3, 15 August 2003, Pages 255-260
Brain Research Bulletin

Cerebral pattern of pro- and anti-inflammatory cytokines in dementias

https://doi.org/10.1016/S0361-9230(03)00088-1Get rights and content

Abstract

The knowledge regarding putative inflammatory component(s) participating in Alzheimer’s disease (AD) and vascular dementia (VAD) is scarce. Recently, we have demonstrated the presence of certain inflammatory cytokines in the cerebrospinal fluid (CSF) of demented patients. Although the initial event(s) triggering the neurodegenerative processes in AD versus VAD may be different and lead to different neuropathological changes, it may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the central nervous system (CNS) may, in turn, act in a similar manner in both diseases, amplifying some pathological changes such as amyloidogenesis and white matter lesions or on the contrary acting as neuroprotective molecules. This review will focus on the intracerebral production of the pro- and anti-inflammatory cytokines interleukin IL-1β, IL-1 receptor antagonist (IL-1ra), IL-6 and TNF-α in dementia, and their relation to gene polymorphism, to cerebral neuronal damage, apoptosis, and to clinical variables of dementia. Our results, which show for the first time strikingly increased CSF levels of TNF-α but not of TNF-β, IL-1β or IL-6 in AD and VAD, may form a conceptual framework for further studies of neuroprotective mechanisms in dementias.

Introduction

With increasing number of elderly in world population, dementia, characterized by progressive loss of memory and higher cortical functions, has given rise to an enormous socioeconomic burden. Approximately 15% of the population over 65 years of age is affected by dementia and among 80-year-olds and older people, 15–20% need institutional care due to severe impairment of cortical functions [17]. Dementia is now the fourth cause of death after cardiovascular diseases, cancer and cerebrovascular diseases [17]. However, dementia is a heterogeneous condition caused by a number of different disorders. Alzheimer’s disease (AD) and vascular dementia (VAD) are the two main causes of dementia affecting between 25–45 and 15–35%, respectively of all demented patients [36].

AD is characterized by atrophy of the brain subsequent to loss of neurons, decrease of the arborization of the dentrites, presence of neurofibrillary tangles and senile plaques. A protein of 42–43 amino acid length, with a high tendency to aggregate, called β-amyloid protein (βA), has been identified as the major component of the senile plaques. βA is derived from a 90 to 140 kDa precursor, called amyloid precursor protein (APP) as reviewed by Banati and Beyreuter [4]. The cause of AD and reasons for its progressive course are still unknown but involvement of the immune system in the pathogenesis of AD has been discussed for years. For example, CD4+ and CD8+ T lymphocytes are present in affected AD brain tissue [26]. In addition, reactive microglial cells have been demonstrated to express class-II molecules of the major histocompatibility complex (MHC) and Fc receptors [27]. Thus, all the appropriate elements necessary for an immune response are present locally in brain of AD patients.

Section snippets

IL-1 and its naturally occurring antagonist, IL-1ra, and IL-6 in AD

Both activated microglia and T lymphocytes can be a source of cytokine production as reviewed by St Pierre et al. [39]. Indeed, IL-1 and IL-6 were detected in AD brains 6., 13., 15.. These cytokines could be involved in the pathogenesis of AD, for example, by promoting inflammatory response as proposed by Vandenabeele and Fiers [48]. IL-1 has been demonstrated to enhance the synthesis of amyloid β-protein precursor mRNA in human endothelial cells [14], suggesting a direct role for this cytokine

Conclusions

Our results show for the first time strikingly increased CSF levels of TNF-α but not of TNF-β, IL-1β or IL-6 in AD and VAD. Intrathecal levels of TNF-α were significantly inversely correlated to the intracerebral apoptosis and neuronal degradation. Furthermore, incubation of human neuronal cells with TNF-α led to production of bcl-2, a molecule known to down-regulate neuronal apoptosis. However, the increased TNF-α protein levels were not associated with the specific gene polymorphism pattern

Acknowledgements

This work was supported by grants from the Göteborg Medical Society, University of Göteborg, The Swedish Association against Rheumatism, the King Gustaf V’s 80-year Foundation, Stroke Foundation, Gamla Tjänarinnor Foundation, John and Brit Wennerströms Foundation, Rune and Ulla Amlöv Foundation, Konrad and Helfrid Johanssons Foundation, Loo and Hans Ostermans Foundation, Clas Groschinsky Foundation, Wilhelm and Martina Lundgrens Foundation, Gun och Bertil Stohnes Foundation, Alzheimer’s

References (51)

  • J. Martinou et al.

    Overexpression of bcl-2 in transgenic mice protects neurons from naturally occurring death and experimental ischemia

    Neuron

    (1994)
  • T. Matsuyama et al.

    Localization of Fas antigen m-RNA induced in postischemic murine forebrain by the in situ hybridization

    Mol. Brain Res.

    (1995)
  • P.L. McGeer et al.

    Reactive microglia in patients with senile dementia of Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR

    Neurosci. Lett.

    (1987)
  • J. McLaurin et al.

    Effect of tumor necrosis factor α and β on humans oligodendrocytes and neurons in culture

    Int. J. Dev. Neurosci.

    (1995)
  • J.K. Relton et al.

    Interleukin-1 receptor antagonist inhibits ischemic and excitotoxic neuronal damage in the rat

    Brain Res. Bull.

    (1992)
  • M. Schwartz et al.

    Tumor necrosis factor facilitates regeneration of injured central nervous system axons

    Brain Res.

    (1991)
  • P. Vandenabeele et al.

    Is amyloidogenesis during Alzheimer’s disease due to an IL-1-/IL-6-mediated “acute phase response” in the brain?

    Immunol. Today

    (1991)
  • A.J. Anderson et al.

    DNA damage and apoptosis in Alzheimer’s disease: colocalization with c-jun immunoreactivity, relationship to brain area, and effect of postmortem delay

    J. Neurosci.

    (1996)
  • R.B. Banati, K. Beyreuter, Alzheimer’s disease, in: H. Kettenman, B.R. Ransom (Eds.), Neuroglia, Oxford University...
  • S.W. Barger et al.

    Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca2+ accumulation

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • N.B. Beamer et al.

    Interleukin-6 and interleukin-1 receptor antagonist in acute stroke

    Ann. Neurol.

    (1995)
  • K. Blennow et al.

    Presence of parieto-temporal symptomatology distinguishes early- and late-onset Alzheimer disease

    Int. J. Geriatr.

    (1991)
  • D.E. Brenneman et al.

    Cytokine regulation of neuronal survival

    J. Neurochem.

    (1992)
  • K. Frei et al.

    On the cellular source and function of interleukin-6 produced in the central nervous system in viral diseases

    Eur. J. Immunol.

    (1989)
  • D. Goldgaber et al.

    Interleukin 1 regulates synthesis of amyloid β-protein precursor mRNA in human endothelial cells

    Proc. Natl. Acad. Sci. U.S.A.

    (1989)
  • Cited by (0)

    View full text