Readers who followed Tom Fagan’s Keystone Symposium coverage of how a particular form of neuroinflammation appears to drive tauopathy while ameliorating amyloid pathology can now take in the full dataset. Tomorrow in Neuron, researchers from Bruce Lamb’s and Richard Ransohoff’s laboratories at the Cleveland Clinic Foundation in Cleveland, Ohio, report results of various experimental approaches suggesting that the fractalkine receptor CX3CR1 on microglial cells might be worth a look as a potential new therapeutic target. Led by first author Kiran Bhaskar, the scientists lay out how activated microglia cause worse tau hyperphosphorylation in mice missing this receptor than in mice that have it. Going beyond the Keystone presentation, the paper reports behavioral impairments in fractalkine receptor-deficient mice; it also implicates the interleukin-1 receptor and contains more mechanistic details on the underlying signaling cascade.

In the September 23 American Journal of Pathology, Sungho Lee and colleagues working with the same senior investigators published the amyloid half of the CX3CR1 story. Curiously, it cuts the opposite way, whereby amyloid pathology in an AD model is milder when the fractalkine receptor is absent in the mouse, probably because the microglia have a greater appetite for phagocytosing amyloid deposits. Together with another recent study on CX3CR1-deficient mice (Fuhrmann et al., 2010), this topic has stimulated scientific discussion about exactly what this receptor does to tau pathology, amyloid pathology, and the survival of embattled neurons. —Gabrielle Strobel.

Reference:
Bhaskar K, Konerth M,1 Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of Tau Pathology by the Microglial Fractalkine Receptor. Neuron. 2010 Oct 7. Abstract

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 2010 Sep 23. Abstract

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  1. We would like to point out our recently published paper, "CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis" (Liu et al., 2010). Similar to Lee et al., we also observe a reduction in fibrillar amyloid plaques and total Aβ levels in an Alzheimer’s mouse model (CRND8) bred to be CX3CR1 deficient.

    Interestingly, regardless of CX3CR1 genotype, we observe that microglia are incapable of fibrillar Aβ phagocytosis; however, they are highly effective at the phagocytosis of protofibrillar Aβ material. CX3CR1 deficiency enhances this selective phagocytic ability both in vitro and in vivo. In contrast to Lee et al., we find that CX3CR1 deficiency led to an increase in microglial proliferation and in the number of microglia surrounding amyloid plaques, which increased overall phagocytic ability. Taken together, this leads us to believe that CX3CR1 deficiency does not enhance the degradation of fibrillar plaques, but rather prevents the formation of new plaques by clearing Aβ seeding material before it can aggregate into plaques.

    In addition, despite the increased number of activated microglia, we did not find any increase in the degree of neuronal or synaptic loss. This suggests that, at least in this mouse model, microglia do not exert a toxic bystander effect as is widely proposed in the literature.

    Our paper (Liu et al., 2010), together with this paper by Lee et al. and a recent paper on CD45-deficient AD mice (Zhu et al., 2011), strongly demonstrate that microglia play a key role in regulating amyloid deposition. This contrasts with a recent study that reports complete microglia ablation has no effect on amyloid deposition (Grathwohl et al., 2009).

    View all comments by Carlo Condello
  2. As best I am aware, this is the first set of studies to examine the effects of the same signaling pathway on the two different AD pathologies independently. The fact that we observed completely opposite effects of CX3CR1 deficiency on Aβ and Tau pathologies suggests that therapeutics strategies aimed at this (and related) pathways may have opposing effects depending upon the stage of disease progression and prevalence of the different brain pathologies. Given recent evidence from imaging and biomarker studies that suggest Aβ and Tau pathologies are differentially induced over a 10-20 year period of time, this provides additional impetus for designing therapeutic strategies and clinical trials aimed at specific stages of disease progression.

References

News Citations

  1. Copper Mountain: Fractious Receptors, Glia, and AD Pathology

Paper Citations

  1. . Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci. 2010 Apr;13(4):411-3. PubMed.
  2. . Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. PubMed.
  3. . 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.

Further Reading

Papers

  1. . Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. PubMed.
  2. . 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.

Primary Papers

  1. . Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. PubMed.
  2. . 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.