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.

View all comments by Bruce Lamb

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...  Read more

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).

References:
Liu Z, Condello C, Schain A, Harb R, Grutzendler J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci. 2010 Dec 15;30(50):17091-101. Abstract

Grathwohl SA, Kälin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. 2009 Nov;12(11):1361-3. Abstract

Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Tan J. CD45 Deficiency Drives Amyloid-{beta} Peptide Oligomers and Neuronal Loss in Alzheimer's Disease Mice J Neurosci. 2011 Jan 1;31(4):1355-1365.

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