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.
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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.
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:
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.