Cerebral pattern of pro- and anti-inflammatory cytokines 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
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