. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J Neurosci. 2011 Aug 3;31(31):11159-71. PubMed.


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  1. This paper by Mildner et al. showed that CCR2 localized at subsets of myeloid cells exert differential roles in plaque pathology. CCR2 localized on peripheral macrophages is required for their infiltration into AD mouse brain parenchyma after total-body irradiation and bone marrow transplantation, but does not affect plaque pathology. In contrast, CCR2 is not required for the recruitment of perivascular macrophages (PVM) to vascular Aβ deposits, but exerts strong effects on plaque clearance.

    A few intriguing lessons emerge from this carefully designed and well-controlled study: 1) The difference between protected versus unprotected (conditioned) brains for the engraftment of peripheral macrophages in the brain is profound. Even in AD mice with significant plaque pathology, the engraftment efficiency of peripheral macrophages in the protected brain seems too low to be detected; 2) The role of PVMs in AD is underappreciated, and this study offers an important clue to their distinct effects on plaque clearance. More studies are needed to further explore their properties and functions in AD pathogenesis; and 3) Cytokine receptors could play differential functions depending on their localization. Besides CCR2 and CX3CR1 on residential microglia, those receptors on peripheral macrophages also play differential roles. Several studies support the idea that there is deficient microglial CX3CR1 in the brain, which reduces plaque load and exacerbates toxicity induced by lipopolysaccharide, the mitochondrial toxin MPTP, soluble Aβ, and phosphorylated-tau (Bhaskar et al., 2010; Cardona et al., 2006; Cho et al., 2011). However, deficient CX3CR1 signaling in intraspinal microglia and monocyte-derived macrophages appears to promote recovery after traumatic spinal cord injury in mice (Donnelly et al., 2011). These findings highlight the importance of cell type- and spatial specificity of cytokine receptors.


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

    . Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006 Jul;9(7):917-24. PubMed.

    . 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.

    . Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci. 2011 Jul 6;31(27):9910-22. PubMed.

  2. I recommend the primary papers, and also I want to add some considerations. In APP/PS1 transgenic mice, we can detect a lot of inflammatory mediators (submitted) in the cortex at five and seven months of age compared to wild-type. It is interesting to note that, in transgenic mice, and in AD, macrophages surrounding the brain can access by crossing the blood-brain barrier, and those cell can be beneficial (or perhaps detrimental) to the patient (McGeer et al., 2006; Viña et al., 2007; Vina et al., 2007). On the other hand, we and others have published (Valles et al., 2008 and 2010) that, in the brain, there not only exist microglia such as macrophages playing a role, but also astrocytes that have their own immune function. We should never forget the role of astrocytes inside the CNS, because otherwise, we are only looking at one type of cell. Astrocytes have many functions inside the CNS, such as contributing to inflammation and oxidative stress. The fact that astrocytes surround amyloid-β in AD patients, and the fact that astrocytes change to reactive astrocytes, engulfing Aβ and destroying it (published by us and others), demonstrates a special role for these cells in AD. Furthermore, inside the brain, neurons, astrocytes, microglia, oligodendroglia, and macrophages from outside are in physiological conditions, so we need to be careful when we look for mechanisms producing or clearing Aβ.

    Neurons are cells with delicate lives. They need the help of astrocytes to survive. Neurons can last for a lifetime, but a decrease in astrocyte support will lead to inefficient elimination of Aβ in the elderly. I believe that microglia are helping the brain in young people, but perhaps in older brain the physiologic mechanisms to eliminate Aβ are weak,, and the elimination of Aβ becomes critical, as suggested by Wyss Coray and collaborators (Tesseur et al., 2006), and us (paper submitted). On the other hand nobody is looking for adult stem cells in elderly AD patients (we want to work on that if we can get funding). Our hypothesis is that, in older brain, oxidative stress and inflammation are playing a cooperative job, such as in young people, but problems start when the two mechanisms are affected by age and/or when either (or both) is destroyed or works poorly due to unfavorable conditions (see next publication of the group Garcia-Lucerga et al., submitted).


    . Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell. 2008 Jan;7(1):112-8. Epub 2007 Nov 21 PubMed.

    . Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. Brain Res. 2010 Feb 2;1312:138-44. Epub 2009 Nov 27 PubMed.

    . Mitochondrial oxidant signalling in Alzheimer's disease. J Alzheimers Dis. 2007 May;11(2):175-81. PubMed.

    . Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide. Antioxid Redox Signal. 2007 Oct;9(10):1677-90. PubMed.

    . Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis. 2006;9(3 Suppl):271-6. PubMed.

    . Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J Clin Invest. 2006 Nov;116(11):3060-9. PubMed.

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