Bon Appétit: Endogenous Antibodies Prod Microglia to Eat Aβ Deposits

What does adaptive immunity have to do with Alzheimer’s disease? It may help curb brain pathology, according to a new study. Mathew Blurton-Jones at the University of California, Irvine, and colleagues had previously found that AD mice lacking B and T cells accumulated up to four times as much amyloid plaque as did littermates whose immune system was intact (see Apr 2015 conference news). In the February 16 Proceedings of the National Academy of Science, the researchers explain why. In mice with normal immune systems, antibodies from the blood enter the brain and trigger microglia to enter a phagocytic state, enabling them to clean up Aβ deposits, the researchers reported.

“The authors have done an elegant set of experiments that demonstrate crosstalk between the adaptive immune system and microglia. That’s very exciting,” said Terrence Town at the University of Southern California, Los Angeles. “Mounting evidence suggests that adaptive immunity will become the next hot topic in Alzheimer’s research,” Town added.

To test if adaptive immune responses influence amyloid pathology, joint first authors Samuel Marsh and Edsel Abud genetically ablated B, T, and natural killer cells in 5xFAD mice by crossing them with Rag2/Il2rγ double knockouts. The latter lack a cytokine receptor and a recombinase gene that are essential for generating these lymphocytes. In addition to the quadrupled plaque load, the Rag-5xFAD offspring accumulated twice as much soluble Aβ as did the 5xFAD mice. Looking for clues to what was happening, the authors analyzed gene expression in the mouse brains and found numerous changes in microglial gene expression. In addition, microglia in the Rag-5xFAD animals had shorter, simpler processes than those in 5xFAD mice, assuming an amoeboid shape characteristic of reactive microglia. The cells ate 40 percent less amyloid than microglia in 5xFAD mice, as seen by immunohistochemical analysis of internalized Aβ. Meanwhile, their production of pro-inflammatory cytokines soared.

Altogether, the data suggested that microglia in the immune-deficient mice shifted from a phagocytic to an inflammatory phenotype. Researchers have linked such microglial shapeshifting to worsening of neurodegenerative disease (see Mar 2013 conference news; Apr 2015 conference news).

What might explain the microglial switch? In 5xFAD mice, but not wild-type or Rag-5xFAD animals, endogenous IgG antibodies clustered around microglia, the authors found. These antibodies did not recognize Aβ. Might they modify glia, Marsh and colleagues wondered? To test this, the authors injected purified IgG from healthy mice into one side of the hippocampi of Rag-5xFAD animals. One week later, plaque load had fallen by half compared with the uninjected side. The authors saw similar results when they transplanted bone marrow from healthy mice into two-month-old Rag-5xFAD animals to restore immune function. Four months later, plaque load in transplanted mice was half that in untreated animals.

Looking for the mechanism, the authors found that IgG from healthy mice stimulated cultured microglia to devour Aβ. Six times as many microglia phagocytosed the peptide, and they ate twice as much on average as IgG-naïve cells. IgG is known to bind to Fc receptors on microglia and activate a signaling pathway through Src tyrosine kinases and PI3K that results in formation of phagosomes (for review, see Garcia-Garcia and Rosales, 2002). In keeping with this, blocking either of those kinases prevented Aβ phagocytosis. The authors concluded that antibodies, irrespective of the antigen they recognize, may stimulate microglial appetites in AD model mice while reducing neuroinflammation.

“[The] findings support the notion that an intact adaptive immune system is important in controlling brain inflammation,” noted Michal Schwartz and Kuti Baruch at the Weizmann Institute of Science, Rehovot, Israel. “These results are in line with observations over the years in experimental models of chronic neurodegenerative diseases,” they wrote to Alzforum (see full comment below).

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. Schwartz’ work supports a role for the choroid plexus in recruiting peripheral immune cells to tame Alzheimer’s pathology (see Sep 2015 news). Intriguingly, transiently opening the blood-brain barrier with ultrasound has been found to stimulate microglia to eat amyloid, also in line with the new findings (see Mar 2015 news). 

Mixed immunoglobulin formulations, such as Baxter International’s Gammagard®, have met with mixed results in clinical trials. Early stage small trials showed potential to clear out brain amyloid, but a subsequent Phase 3 trial missed cognitive and functional endpoints (see Aug 2013 conference news; Gammagard® Phase 3 results). Development of Gammagard® for Alzheimer’s has been discontinued, but a Phase 2/3 study with a different blood product is ongoing in Spain (Gamunex). Blurton-Jones and colleagues believe that this approach may deserve investigation in prodromal AD, perhaps in conjunction with ultrasound to open the blood-brain barrier.—Madolyn Bowman Rogers

Comments

  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., 2008; Chiu 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.

    References:

    Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. 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.

    Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.

    Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. 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.

    Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC. 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.

    Ip CW, Beck SK, Volkmann J. 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 Kuti Baruch 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.

    References:

    Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. 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). 

    References:

    Levites Y, Smithson LA, Price RW, Dakin RS, Yuan B, Sierks MR, Kim J, McGowan E, Reed DK, Rosenberry TL, Das P, Golde TE. 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.

    Krueger M, Härtig W, Reichenbach A, Bechmann I, Michalski D. 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.

    Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, Steinberg GK, Barres BA, Nimmerjahn A, Agalliu D. 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.

    Gilad R, Lampl Y, Eilam A, Boaz M, Loyberboim M. 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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References

News Citations

  1. Could Adaptive Immunity Set the Brakes on Amyloid?
  2. Microglia Activation—Venusberg Meeting Questions M1, M2 Designations
  3. Microglia—Who Are You Really? New Clues Emerge
  4. Does Peripheral Immune Activity Tame Alzheimer’s Disease?
  5. Stop, Hey, What’s That Sound? ... Amyloid Is Going Down?
  6. Clinical Trials Roundup: Four Hits, No Home Runs

Research Models Citations

  1. 5xFAD (B6SJL)

Therapeutics Citations

  1. Gamunex

Paper Citations

  1. García-García E, Rosales C. Signal transduction during Fc receptor-mediated phagocytosis. J Leukoc Biol. 2002 Dec;72(6):1092-108. PubMed.

Other Citations

  1. Gammagard®

External Citations

  1. Gammagard® Phase 3 results

Further Reading

Primary Papers

  1. Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, Fote GM, Lau L, Weinger JG, Lane TE, Inlay MA, Poon WW, Blurton-Jones M. 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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