In continuing their search for novel inhibitors of CD40 expression on macrophages/microglia, Wesemann and colleagues present data showing that SOCS-1 overexpression is able to mitigate IFN-gamma-induced CD40 expression in a macrophage cell line. It seems that this inhibition is accomplished at the protein, mRNA, and promoter activity levels. Investigation into upstream signaling events revealed that the STAT-1alpha and NF-kappaB pathways were both inhibited by SOCS-1 overexpression. Quite interestingly, exogenous application of TNF-alpha- which these authors show activates the NF-kappaB pathway but not the STAT-1alpha cascade- is not able to rescue SOCS-1 overexpression inhibition of IFN-gamma-induced CD40 expression. This result is important because it further confirms that activation of both pathways is required for efficient IFN-gamma induction of CD40. Given the importance of CD40-CD40L interactions in the pathogenesis of AD, this study is germane in that SOCS-1 and/or its downstream transduction molecules may be good pharmacotherapeutic targets for interrupting CD40...  Read more

In continuing their search for novel inhibitors of CD40 expression on macrophages/microglia, Wesemann and colleagues present data showing that SOCS-1 overexpression is able to mitigate IFN-gamma-induced CD40 expression in a macrophage cell line. It seems that this inhibition is accomplished at the protein, mRNA, and promoter activity levels. Investigation into upstream signaling events revealed that the STAT-1alpha and NF-kappaB pathways were both inhibited by SOCS-1 overexpression. Quite interestingly, exogenous application of TNF-alpha- which these authors show activates the NF-kappaB pathway but not the STAT-1alpha cascade- is not able to rescue SOCS-1 overexpression inhibition of IFN-gamma-induced CD40 expression. This result is important because it further confirms that activation of both pathways is required for efficient IFN-gamma induction of CD40. Given the importance of CD40-CD40L interactions in the pathogenesis of AD, this study is germane in that SOCS-1 and/or its downstream transduction molecules may be good pharmacotherapeutic targets for interrupting CD40 signaling. The authors themselves mention a study where SOCS-1 was shown to inhibit TNF-alpha signaling (Morita et al., 2000). This begs the question of how specific SOCS-1 is for down regulating CD40 expression as opposed to its effect on other TNFR/NGFR superfamily members such as TNFR-I, TNFR-II, and/or p75 NTR. Such future investigation would be important to give more insight into how viable SOCS-1 is as a pharmacotherapeutic target for disrupting CD40 signaling in AD.

View all comments by Terrence Town

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   Read more

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.

View all comments by P.L. McGeer

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...  Read more

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.

View all comments by Daniel Watterson