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15 November 2000. CD40 is a member of the TNF receptor superfamily, which includes TNFR-1, TNFR-2, Fas, CD27, RANK, DR4 (TRAIL-R1), DR5 (TRAIL-R2), and DR6, as well as assorted decoy receptors (e.g., DcR-1/TRAIL-3). The TNF receptor superfamily is characterized by an extracellular domain containing two to six repeats of a cysteine rich motif. Many of these receptors are expressed on neurons in animal models of injury, and recent reports have demonstrated their expression in the AD brain.
It is clear that microglial cells play a key role in modulation and mediation of immune responses in the brain. Michael Mullan’s group has previously demonstrated that interferon-g (IFN-g) increases CD40 expression in cultured brain microglia, and that microglial activation by CD40 ligand (CD40L) in the presence of IFN-g results in increased TNFa production and TNFa?mediated cortical neuron toxicity in vitro. Given recent evidence for the role of microglial activation in Aβ clearance in active and passive immunization studies in animal models of AD, and pending studies on the clinical applicability of this approach, the mechanisms and secondary consequences of microglial activation by Aβ are of current interest.
In this study (Abstract 299.13), the authors demonstrate increased expression of CD40 in cultured brain microglia treated with very low doses of β-amyloid (Aβ) 1-40 or 1-42 peptides (500nm). In parallel with previous observations, microglial activation by CD40L in the presence of Aβ resulted in increased TNFa production and neurotoxicity in neuronal co-cultures. Moreover, CD40 expression was also increased on microglia in a transgenic mouse model of AD (Tg APPsw). Crosses of Tg APPsw mice with CD40L-deficient mice exhibited reduced microglial activation in tissue sections, and reduced TNFa release in microglial cultures derived from these animals. Interestingly, tau hyperphosphorylation, e.g., as detected with AT-8, was decreased in 8 month old Tg APPsw/CD40L-deficient animals. These data suggest that Aβ-stimulated microglial activation and TNFa production is dependent on CD40L, and that CD40-CD40L interactions may play a role in AD pathogenesis.
Further References:
Mullan M, Town T, Paris D, Crawford F, Tan J. Department of Psychiatry. The Roskamp Institute, Tampa, FL, USA. The CD40 pathway mediates β-amyloid-induced microglial activation. Society for Neuroscience Abstract 299.13.
Tan J, Town T, Paris D, Placzek A, Parker T, Crawford F, Yu H, Humphrey J, Mullan M. Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis. Journal of Neuroimmunology, 1999 Jun 1;97(1-2):77-85.
Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M. Microglial activation resulting from CD40-CD40L interaction after β-amyloid stimulation. Science 1999 Dec 17;286(5448):2352-5.
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