CD40-CD40L interaction in Alzheimer's disease.
Increasing evidence supports a role of the CD40 receptor-CD40 ligand (CD40-CD40L) interaction in the pathogenesis of Alzheimer's disease (AD). It has previously been shown that this dyad acts synergistically with the Alzheimer amyloid-beta peptide to promote microglial activation. Reactive microglia produce potentially neurotoxic substances such as tumor necrosis factor alpha and the reactive oxygen species nitric oxide, which can induce bystander neuronal injury at high levels. When a transgenic mouse model of AD is crossed with an animal deficient in CD40L, the resulting phenotype is deficient in the gliosis observed in a mouse model of AD in which CD40L is present. Additionally, these crossed animals have complete absence of AD-like neuronal Tau hyperphosphorylation, a marker of the preneuronal tangle pathology in AD patients. This suggests that the CD40-CD40L system is a critical enhancer of microglial activation in an AD transgenic mouse model and that such activation is associated with an increase in a key indicator of neuronal stress. Conversely, the finding that reduced CD40-CD40L interaction is associated with reduced chronic microgliosis and Tau hyperphosphorylation supports the view that, in general, mechanisms that reduce microgliosis will be beneficial in AD.
Tan
Jun
J
The Roskamp Institute, Department of Psychiatry, University of South Florida, 3515 East Fletcher Avenue, Tampa, Florida 33613, USA. jtan@hsc.usf.edu
Town
Terrence
T
Mullan
Mike
M
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D019013:CD40 Antigens; D023201:CD40 Ligand