Working in cultured microglial cells, they found that both Aβ[1-40] and Aβ[1-42], either added exogenously or already present in microglia from transgenic mice, markedly increased expression of the CD40 receptor. When the Aβ-stimulated microglia were treated with a CD40 ligand, significantly more cultured neurons died and production of tumor necrosis factor α (TNF-α) increased to concentrations known to cause cell injury. Blockade of TNF-α eliminated this cell death.

The authors then carried their experiments into an in vivo model. They crossed a mouse line that features significant Aβ deposition (Tg APP[SW]) with mice deficient in CD40 ligand and found a reduction in TNF-α production in cultured microglia from these animals. Finally, the authors showed that crossing Tg APP[SW] mice with those deficient in CD40 ligand resulted in a reduction in the early abnormal tau phosphorylation seen in TG APP[SW] mice.

The authors take this evidence to suggest that the CD40-CD40 ligand interaction--primed by Aβ-and a resulting microglial-mediated inflammatory process-occurs early in Alzheimer's pathogenesis. This raises the possibility that therapeutic approaches to blocking the CD40 signaling pathway might suppress neurodegeneration in Alzheimer's.-Hakon Heimer.

Reference: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 beta-amyloid stimulation. Science 1999 17 Dec;286:2352-5. Abstract