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

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  1. Tan et al. have created doubly transgenic mice which overexpress APP(sw) and are deficient in CD40 ligand (CD40L). They find that these doubly transgenic mice have a greatly reduced burden of amyloid deposits compared to the singly transgenic APP mice. Treating singly transgenic PSAPP mice with a CD40L antibody produced a similar reduction in burden. This reduction was accompanied by increased nonamyloidogenic APP processing, increased circulating levels of Aβ and decreased glial activation. CD40L-CD40 interactions are known to stimulate microglia. One interpretation is that reducing microglial activation generally reduces the amyloid burden in APP transgenic mice. The previously reported reduction in burden brought about by ibuprofen treatment is consistent with this interpretation. But that does not fit with the clearance of deposits brought about by vaccination with Aβ, which stimulates microglial phagocytosis. It also does not fit with enhancement of the burden in mice doubly transgenic for APP and the complement inhibiting-receptor related protein (sCrry) (see news story).

    Clearly, there is much to be learned about the relationships among overproduction of APP in neurons of transgenic mice, the generation of Aβ from the overproduced APP, and the clearance of Aβ by microglial phagocytosis.. Even when these relationships are properly understood, it will be problematic translating them to treatment strategies for Alzheimer’s disease. Transgenic mice overexpressing APP are, at best, a partial model of AD, and manipulations which are beneficial in such transgenic mice may have harmful effects in AD patients. This is already apparent through vaccination experiments, in which some AD cases developed an encephalitis not seen in transgenic mice, presumably due to an autoimmune reaction (see live discussion). Understanding the differences between AD and APP transgenic mouse pathology is a vital part of the equation.

  2. The recent Nature Neuroscience paper by Michael Mullan and colleagues entitled "Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice" (see Abstract) presents exciting results showing a correlation between reduction in CD40 ligand (CD40L) levels and reduction in both inflammatory pathology and Aβ/β-amyloid pathology in the brains of transgenic mouse models of Alzheimer’s disease (AD). CD40L levels were reduced by either a genetic approach (crossing APP Tg2576 mice with CD40L-knockout mice) or a pharmacological approach (injecting PSAPP mice with anti-CD40L antibody). The results seen with both approaches were congruent. The major findings were that mice with diminished CD40L levels exhibited:

    • decreased astrocytosis and microgliosis;
    • diminished Aβ load and b-amyloid plaque burden;
    • decreased amyloidogenic processing of APP;
    • increased circulating levels of Aβ.

    The results support the idea that CD40L, a key immunoregulatory molecule that is an important mediator of microglial activation, contributes to amyloid plaque pathology. The data also reinforce the idea that uncontrolled or abnormal glial activation (astrogliosis and microgliosis) can have detrimental consequences, and that targeting neuroinflammatory signaling cascades may be useful in drug development strategies for AD. While the results do not provide a validated drug discovery target, the rare but powerful experimental approaches used by the investigators, i.e., complementary use of genetics-based experimental approaches and biological modulation by administration of targeted exogenous molecules (pharmacological approach), provide a firm foundation for future work by medicinal chemists, who are now alerted to this particular pathway as a potential drug discovery target.

References

News Citations

  1. Aβ Primes an Inflammatory Pump
  2. Soc for Neurosci Ann Mtg: β-Amyloid Triggers CD40 Expression in Microglia

Further Reading

Papers

  1. . Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. J Immunol. 2002 Sep 1;169(5):2354-60. PubMed.

Primary Papers

  1. . Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci. 2002 Dec;5(12):1288-93. PubMed.