. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1316-25. Epub 2016 Feb 16 PubMed.


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  1. In this elegant and important study, Samuel E. Marsh and colleagues demonstrate that deficiency in the adaptive arm of the immune system exacerbates pathology in an Alzheimer’s disease mouse model.

    While the hypothesis that adaptive immunity plays a role in Alzheimer's disease pathophysiology is certainly not new, the present study significantly contributes to alleviate the long-held confusion in the field between the role of local neuroinflammatory responses within the brain, which are part of pathology, and systemic immune activity. Marsh et al.’s findings support the notion that an intact adaptive immune system is important in controlling brain inflammation, and that deficiency in the adaptive immune system in AD is associated with exacerbated brain inflammation, microglial phenotype switch, and their reduced phagocytic activity. These results are in line with other observations over the years in experimental models of chronic neurodegenerative diseases (Beers et al., 2008Chiu et al., 2008; Ip et al., 2015). 

    These findings are also in line with our recent studies, demonstrating that transient reduction of systemic immune suppression (Baruch et al., 2015), or utilizing an immune checkpoint blockade approach in AD mouse models (Baruch et al., 2016), can mount a systemic immune response that leads to reduction in neuroinflammation, clearance of amyloid-β plaques, and reversal of cognitive decline.

    While it seems that under neurodegenerative conditions, where microglial activation and gliosis are robust, there is a critical need for systemic immune activity in containing neuroinflammation, these findings may also point to a more general concept: Adaptive immunity plays an essential role in the maintenance of life-long brain plasticity. Collectively, these findings could support the notion that neurodegenerative diseases are dormant long before their onset as long as the immune system is effective; deficiency in adaptive immunity might lead to an earlier onset of neurodegenerative diseases.


    . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    . Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.

    . CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15558-63. Epub 2008 Sep 22 PubMed.

    . T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17913-8. Epub 2008 Nov 7 PubMed.

    . Lymphocytes reduce nigrostriatal deficits in the 6-hydroxydopamine mouse model of Parkinson's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1633-43. Epub 2015 Aug 20 PubMed.

    View all comments by Michal Schwartz
  2. The paper is very interesting and further supports an important role for microglia in AD pathology. Here it appears that adaptive immunity (e.g., B-cell-derived antibodies) stimulates microglial phagocytosis/clearance of Aβ/amyloid in the mouse brain. This is relevant to our finding that antibodies stimulate microglial clearance of tau (see Luo et al., 2015). Though the authors did not test for tau clearance, I would predict they would see the same phenomenon had they substituted pathological tau species for Aβ. This work speaks to the important cross-talk between the adaptive and innate immune systems.


    . Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015 Jun 9;5:11161. PubMed.

    View all comments by Steven Paul
  3. This is a very interesting paper. In her news piece Madolyn Rogers writes “It is unclear how the antibodies enter the brain. The authors found no breach of the blood-brain barrier, but did see the antibody accumulate in the choroid plexus of 5xFAD mice, hinting this could be their route of entry.” In this respect, it is interesting that a recent report states that active exchange between blood and brain under normal physiological conditions is indicated by the fact that, for example, steady-state brain levels of peripherally administered antibodies are approximately 0.1 percent of those in the plasma (Levites et al., 2006). Such evidence does not suggest that the BBB is not compromised under certain pathological conditions, only that the precise nature of the damage is incompletely understood (Krueger et al., 2013; Knowland et al., 2014; Gilad et al., 2012). 


    . Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J. 2006 Dec;20(14):2576-8. Epub 2006 Oct 26 PubMed.

    . Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS One. 2013;8(2):e56419. Epub 2013 Feb 26 PubMed.

    . Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron. 2014 May 7;82(3):603-17. Epub 2014 Apr 17 PubMed.

    . SPECT-DTPA as a tool for evaluating the blood-brain barrier in post-stroke seizures. J Neurol. 2012 Oct;259(10):2041-4. Epub 2012 Feb 10 PubMed.

    View all comments by Jürgen Götz

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