Aβ levels and amyloid plaque load can be reduced significantly in animal models of Alzheimer's disease by interfering—either genetically or pharmacologically—with the immunoregulatory molecule CD40 ligand, according to a report in the current Nature Neuroscience by Jun Tan, Terrance Town, Michael Mullan, and colleagues at the University of South Florida in Tampa and at Yale University in New Haven, Connecticut. Follow-up findings are also being presented here at the Neuroscience Conference-see below.
Previous research led by Mullan and others (see related news item A; and related news item B) had indicated that Aβ upregulates levels of the CD40 receptor on the surface of microglia, and that CD40 interaction with its ligand (CD40L) played a role in the activation of microglia. As might be expected, however, the cause-and-effect relationship is not so simple, because CD40 and CD40L are then found in and around amyloid plaques in AD brain, suggesting that they may play a subsequent role in Aβ production and amyloidogenesis. The question of whether microglial activation is good or bad in AD pathogenesis is being debated, with different pieces of evidence pointing both at pathogenic and at protective aspects of microglial activation.
In the current experiments, the researchers sought to discover whether manipulating CD40L could affect Aβ levels or amyloid pathology in transgenic models of AD. They first crossed TgAPPswe mice (which carry the Swedish APP mutation and overproduce the toxic forms Aβ40 and Aβ42) and mice deficient in CD40L. These mice showed significantly reduced Aβ levels and amyloid plaque burden, as well as decreased gliosis and astrocytosis.
In a second set of experiments, the researchers showed that they could achieve the same effect pharmacologically. Mice transgenic for both the Swedish mutation and the M146L presenilin 1 mutation (PSAPP mice) were treated with an anti-CD40L antibody, with a resulting marked reduction in amyloid plaque burden and in gliosis. This was associated with an increase in circulating Aβ levels and a shift in APP processing from amyloidogenic to nonamyloidogenic fragments.
On Wednesday at the Neuroscience Conference, J.T. Roach from Mullan’s group will report in a talk (722.2) on behavioral deficits in PDAPP mice improving somewhat when treated with an antibody to CD40 ligand, and on Thursday, Jun Tan is presenting a poster on the role of the CD40 signaling pathway on neuronal differentiation and survival.
This last finding suggests that CD40L could act directly on neuronal APP processing, a possibility that the researchers explored further in neuroblastoma cells expressing human wild-type APP. In this in vitro system, the addition of CD40L shifted APP processing away from nonamyloidogenic α-C-terminal fragments and toward amyloidogenic β-C-terminal fragments. The addition of anti-CD40L antibody negated this shift.
"The main point of this paper is that the CD40-CD40 ligand interaction promotes the pathological hallmark of Alzheimer's disease, the β-amyloid plaque. The potential importance of this work is that it opens up a novel therapeutic approach for Alzheimer's disease, aimed at blocking this pathway," said author Tan.
Senior author Mullan added another emphasis to the work: "It places not just inflammation, but the immune response per se, as central to Alzheimer's disease pathogenesis."—Hakon Heimer and Gabrielle Strobel
- Wesemann DR, Dong Y, O'Keefe GM, Nguyen VT, Benveniste EN. Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. J Immunol. 2002 Sep 1;169(5):2354-60. PubMed.
- Tan J, Town T, Crawford F, Mori T, Delledonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci. 2002 Dec;5(12):1288-93. PubMed.