Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, Ransohoff RM, Gan L. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem. 2011 Sep 16;286(37):32713-22. Epub 2011 Jul 19 PubMed.
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University of Southern California
Cho et al. offer a rather iconoclastic view of the role that fractalkine signaling plays in AD-like pathology. The authors open with data from postmortem AD versus control brains, showing that CX3CL1 (cognate fractalkine ligand) protein levels are significantly reduced in AD hippocampus and frontal cortex. The bulk of the authors' findings are in a crossed mouse paradigm, where they crossed mhAPP line J20 AD model mice (Mucke et al., 2000) with CX3CR1 receptor knockouts. Principal findings in crossed mice include increased activation of microglia (presumed brain-resident populations), increased mRNA levels of innate pro-inflammatory cytokines TNF-α and IL-6, increased phospho-tau levels, and inverse correlation of TNF-α mRNA abundance with dentate gyrus calbindin abundance. This work certainly has merit and value, primarily because it contrasts with a recent report (Fuhrmann et al., 2010). Specifically, those authors crossed the LaFerla 3xTg-AD mouse (Oddo et al., 2003) with PS1 knock-in and Thy1-YFP transgenic mice, and found that deletion of CX3CR1 spared neuronal loss. While the authors do discuss this point briefly, the dissimilar results between the two studies are nonetheless salient.
The authors convincingly show reduced CX3CL1 protein abundance in AD cases versus controls. However, their CX3CR1 data do not reach statistical significance in the AD patients. As the authors duly note, levels of the receptor need not parallel ligand abundance. Yet, this may obscure the rationale for knocking out CX3CR1 in the J20 mice, as it seems more logical from the human AD results to make CX3CL1-deficient J20 mice. Future studies should go on to check levels of an intracellular mediator of CX3CR1 signaling in the J20 mice versus WT and in the AD versus control samples to be more definitive about the signaling conclusions that are drawn.
Interestingly, Bruce Lamb and Richard Ransohoff are now developing a model wherein CX3CR1 signaling plays dual roles in AD-like pathology. When considering Aβ plaques, they find that the receptor promotes pathology (Lee et al., 2010); however, in terms of tauopathy, CX3CR1 actually dampens it (Bhaskar et al., 2010). On the translational front then, it may be difficult to develop a fractalkine signaling pathway pharmacotherapeutic approach for human AD, given these opposing effects. Perhaps timing is the key here, and by administering a therapeutic early versus late in the disease course, the beneficial effects could be selectively targeted.
References:
Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000 Jun 1;20(11):4050-8. PubMed.
Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. PubMed.
Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, Laferla FM, Kretzschmar H, Herms J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci. 2010 Apr;13(4):411-3. PubMed.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol. 2010 Nov;177(5):2549-62. PubMed.
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