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Could Adaptive Immunity Set the Brakes on Amyloid?

Series - International Conference on Alzheimer's & Parkinson’s Diseases 2015:

In the last few years, neuroinflammation has surged to the forefront of Alzheimer’s disease research. In dozens of presentations at the 12th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 18-22 in Nice, France, researchers grappled with the complexities of how the immune system can both speed and slow disease progression. At this point, there are more questions than answers, scientists agreed. One emerging theme was an unexpected involvement of the adaptive immune system in AD, supported by genetic and animal studies. Researchers also debated, again, what role peripheral macrophages play in cleaning up the brain. Others focused on microglia, trying to parse what makes these cells a force for good rather than ill in the diseased brain, and what role the risk factor TREM2 plays in this (see Part 10 of this series). Overall, the data at AD/PD generated excitement but no consensus.

“The talks represented excellent science, but we have a long way to go yet to arrive at a unifying theory of inflammation in AD,” Cynthia Lemere of Brigham and Women’s Hospital, Boston, told Alzforum, expressing a common sentiment.

Genetic studies have driven the recent interest in inflammation. In Nice, Rudolph Tanzi of Massachusetts General Hospital, Charlestown, added new data highlighting the role the immune system plays in disease risk. He presented recent results from the ongoing Alzheimer’s Genome Project, which now has sequenced whole genomes from 1,480 people in 437 families with inherited AD. Unlike GWAS, which find risk markers but usually do not identify functional variants, whole-genome sequences allow researchers to more easily home in on the polymorphisms that cause disease. These projects also generate a huge amount of data. In the case of the Alzheimer’s Genome Project, that amounts to about half a petabyte so far, or 500,000,000,000,000 bytes—and with that come technical challenges to clean up and analyze the findings, Tanzi noted. In preliminary analyses, the researchers focused on known GWAS risk loci. So far, they have turned up 180 rare variants in these genes that segregate with disease in families and are predicted to alter protein function. Many of the affected genes are involved in phagocytosis and chemokine signaling. “Immune genes are the fastest-growing set in AD,” Tanzi told the audience.

The researchers also looked for structural variations, such as duplications or deletions, that segregated with disease. They found three hits with genome-wide significance. Unexpectedly, all were genes involved in adaptive immunity: the T cell receptor α, the IgG heavy chain, and the IgG κ gene.

Adaptive Immunity Quashes Amyloid.

5xFAD mice lacking B and T cells (right) accumulate four times the volume of amyloid plaques (red) in their dentate gyrus, compared to mice with intact immune systems (left). [Image courtesy of Samuel Marsh and Mathew Blurton-Jones.]

How might adaptive immune genes influence AD? Tanzi speculated that defects in this system could leave the brain more vulnerable to infiltration by pathogens such as the candida fungus and herpes simplex virus (see Feb 2011 webinar). One previous study proposed that a normal function of Aβ is to attack microbes, and that it gets released in response to infection (see Mar 2010 news). Tanzi proposed an immunogenetic hypothesis of Aβ, in which genetic variants first compromise immune function in the brain, which over time leads to low-grade infections. In response, neurons might pump up Aβ production, kicking off pathology and eventually leading to plaques and tangles. Tanzi is pursuing this hypothesis with Robert Moir at MGH. In preliminary studies, they have found that injecting salmonella bacteria into the hippocampus of 5xFAD mice rapidly seeds amyloid plaques, Tanzi said.

To date, few researchers have studied effects of the adaptive immune system in AD, since B and T cells are confined to the bloodstream and are believed to stay outside the blood-brain barrier under most circumstances. One researcher who has focused on this has been Michal Schwartz at the Weizmann Institute of Science in Rehovot, Israel. She has long championed a role for the peripheral immune system in neurodegenerative disease. Her previous studies hinted that T cells may influence brain microglia via cytokines and aid in injury repair (see Jul 2006 news; Sep 2009 news). In Nice, other labs took up the cause, emphasizing the importance of adaptive immune cells in AD. These talks received an enthusiastic response from the audience, who peppered speakers with questions.

Samuel Marsh works with Mathew Blurton-Jones at the University of California, Irvine. He made a case for adaptive immunity controlling AD pathology. Marsh became interested in this when he crossed 5xFAD mice with a transgenic strain missing B and T cells in order to facilitate stem cell studies. The latter mice, Rag2-/-/IL2Rγ-/-, lack two genes essential for the generation of lymphocytes (see Mazurier et al., 1999). Marsh noticed that the Rag-5xFAD offspring had twice as much soluble Aβ40 and Aβ42 and up to four times the volume of amyloid plaque in their brains as the 5xFAD controls. Looking for the mechanism, Marsh found increases in pro-inflammatory cytokines such as IL-1β, IL-6, and TNFα in their brains. The hybrids also had slightly more activated, Iba+ microglia in their dentate gyrus. The results suggest that adaptive immune cells communicate with the CNS and affect inflammation there, Marsh concluded. Another possibility is that antibodies normally cross the blood-brain barrier and aid amyloid clearance, he suggested. He is now transplanting bone marrow from young and old mice into these animals to find out if this will ameliorate pathology.

How might the adaptive immune system communicate with the brain? Perhaps through effects on peripheral phagocytes, suggested Kuti Baruch, who works with Schwartz. Previous studies reported that peripheral monocytes can infiltrate brain tissue to mop up amyloid, taking over cleanup duties from sluggish microglia (see Jun 2008 news; Apr 2011 news; Aug 2011 news). In earlier work, Schwartz and colleagues found that the choroid plexus tissue that lines the brain’s ventricles expresses chemokines and adhesion molecules that attract monocytes to sites of injury and help them enter the brain (see Shechter et al., 2013). Expression of these trafficking molecules depends on interferon-γ released by memory effector T cells that cozy up to the choroid plexus epithelium (see Kunis et al., 2013). Aging alters this cross-talk between T cells and choroid plexus, shifting signaling from IFN-γ to IL-4 and creating a more pro-inflammatory milieu (see Aug 2014 news; Baruch et al., 2013).

In Nice, Baruch suggested that in AD, problems with the choroid plexus might hinder its recruitment of monocytes. To test this idea, he examined 5xFAD mice and indeed found less IFN-γ at the choroid plexus, as well as a steep drop in the expression of various leukocyte-recruiting molecules, such as ICAM1, VCAM1, CXCL10, CD73, and CCL2. To see if he could reverse this, Baruch injected 6-month-old mice weekly with glatiramer acetate (GA). This multiple sclerosis drug stimulates T cells. In treated animals, more monocytes infiltrated the brain, became macrophages and surrounded plaques. Inflammation dampened, plaques shrank, and behavioral test performance improved. This benefit lasted for up to a month after injection, Baruch said. He cautioned, however, that daily GA injections had the opposite effect, suppressing leukocyte recruitment and exacerbating inflammation. Future modulation of the immune system would have to be precisely calibrated to benefit patients, he concluded.

In a similar vein, a poster presented by Guillaume Dorothee of INSERM, Paris, emphasized the importance of T cells in modulating the phagocytes’ response in AD. Dorothee and colleagues depleted T regulatory cells in APPPS1 mice, and saw fewer microglia around amyloid plaques along with an earlier onset of cognitive problems. Conversely, when they selectively amplified the T regulatory cell population by treating with low-dose IL-2, more microglia surrounded plaques and cognitive deficits held off. Although the precise mechanisms of action of T regulatory cells are still under investigation, the data highlight the therapeutic potential of innovative Treg-based immunotherapy for AD, Dorothee told Alzforum.

Do T cells exert all their influence from outside the brain? Perhaps not. Maria-Teresa Ferretti, who works with Roger Nitsch at the University of Zurich, noted that several groups have reported T cells in the parenchyma of AD brains, although the idea remains controversial (for review, see Ransohoff and Engelhardt, 2012; Togo et al., 2002). Ferretti examined human postmortem brain samples, and found higher numbers of T cells in hippocampal sections from AD patients versus controls. To study this further, she turned to aged APP transgenic mice. These animals had about twice as many T cells in their brain tissue as did wild-type mice, she reported. How did they get in? T cells were not correlated with micro-hemorrhages, nor did they get stuck in blood vessels or perivascular space, Ferretti found. Instead, she saw an increase of adhesion molecules such as ICAM-1 and VCAM-1 in the brain’s blood vessels, and concluded that the endothelium in AD brains encourages entry of T cells. What the cells are doing is less clear. Ferretti saw little evidence that they proliferated. She analyzed their markers and found the cells expressed low levels of IFN-γ, suggesting they were not cytotoxic and instead might play a regulatory function.

Overall, AD/PD talks pointed toward a role for adaptive immunity in AD. “The adaptive process appears to be less robust than innate immunity, in terms of the number of immune cells in brain. But regardless, it has a major impact on the downstream events in pathogenesis,” noted Lemere in an email to Alzforum.

Other scientists added nuance to the idea that peripheral macrophages aid phagocytosis in the brain. In a poster, Stefan Prokop, Kelly Miller and Frank Heppner of Charité University Medicine, Berlin, described ablating microglia in 5-month-old APPPS1 mice through a genetic cross. In response, peripheral monocytes infiltrated and repopulated the brain. However, these new cells did not surround amyloid plaques, nor did they lower the Aβ burden. Even treating the mice with anti-Aβ antibodies failed to activate these macrophages. Additional triggers might be necessary to stimulate macrophages to chew up Aβ, the authors suggested.

Researchers disagree on the role of macrophages versus microglia in AD. One problem is that many studies distinguish the cell types using markers that are not always reliable, Todd Golde of the University of Florida, Gainesville, wrote to Alzforum. In ongoing studies, researchers are attempting to better delineate these immune cells (see Feb 2015 conference news). For the latest on microglial studies, see Part 10 of this series.—Madolyn Bowman Rogers

Comments

  1. The idea that adaptive immunity might play a role in Alzheimer's disease is not a new hypothesis (see Foley et al., 1988; Bradford et al., 1989; Fillit et al., 1987; Itagaki et al.. 1988). Ishii described the presence of immunoglobulins and complement in plaques almost 40 years ago (Ishii and Haga, 1976; Ishii and Haga, 1984); and neither is the hypothesis that inflammation and the innate immune system play a role a new development (McGeer et al., 1989; Itagaki et al., 1989; Fillit et al., 1991).

    What is needed now are novel clinical trials to test new agents that attack the neuroinflammatory response, especially since most if not all clinical trials thus far in this space have failed, including prednisone, NSAIDs, etc. ADDF is interested in funding novel proposals, both clinical and preclinical, to reduce neuroinflammation. Please see the Alzdiscovery website for information on how to apply, and to review our currently funded research portfolio in drug discovery and development for neuroinflammation.

    References:

    Foley P, Bradford HF, Docherty M, Fillit H, Luine VN, McEwen B, Bucht G, Winblad B, Hardy J. Evidence for the presence of antibodies to cholinergic neurons in the serum of patients with Alzheimer's disease. J Neurol. 1988 Nov;235(8):466-71. PubMed.

    Bradford HF, Foley P, Docherty M, Fillit H, Luine VN, McEwen B, Bucht G, Winbald B, Hardy J. Antibodies in serum of patients with Alzheimer's disease cause immunolysis of cholinergic nerve terminals from the rat cerebral cortex. Can J Neurol Sci. 1989 Nov;16(4 Suppl):528-34. PubMed.

    Fillit HM, Kemeny E, Luine V, Weksler ME, Zabriskie JB. Antivascular antibodies in the sera of patients with senile dementia of the Alzheimer's type. J Gerontol. 1987 Mar;42(2):180-4. PubMed.

    Itagaki S, McGeer PL, Akiyama H. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer's disease brain tissue. Neurosci Lett. 1988 Sep 12;91(3):259-64. PubMed.

    Ishii T, Haga S. Immuno-electron microscopic localization of immunoglobulins in amyloid fibrils of senile plaques. Acta Neuropathol. 1976 Nov 15;36(3):243-9. PubMed.

    Ishii T, Haga S. Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol. 1984;63(4):296-300. PubMed.

    McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system response in Alzheimer's disease. Can J Neurol Sci. 1989 Nov;16(4 Suppl):516-27. PubMed.

    Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol. 1989 Oct;24(3):173-82. PubMed.

    Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G. Elevated circulating tumor necrosis factor levels in Alzheimer's disease. Neurosci Lett. 1991 Aug 19;129(2):318-20. PubMed.

    View all comments by Howard Fillit

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References

News Citations

  1. Microglia—Who Are You Really? New Clues Emerge
  2. Paper Alert: Aβ’s Day Job—Slayer of Microbes?
  3. The Well-Tempered Immune System: Taming Microglia to Fight AD
  4. ALS: T Cells Step Up
  5. Macrophages Storm Blood-brain Barrier, Clear Plaques—or Do They?
  6. CCR2-Positive Macrophages: White Knights of Phagocytes?
  7. Perivascular Macrophages: The Real Amyloid Clean-Up Crew?
  8. Choroid Plexus May Hold a Key To Aging Brain
  9. Microglia in Disease: Innocent Bystanders, or Agents of Destruction?

Webinar Citations

  1. Herpes Simplex and Alzheimer’s—Time to Think Again?

Research Models Citations

  1. 5xFAD (B6SJL)

Paper Citations

  1. Mazurier F, Fontanellas A, Salesse S, Taine L, Landriau S, Moreau-Gaudry F, Reiffers J, Peault B, Di Santo JP, de Verneuil H. A novel immunodeficient mouse model--RAG2 x common cytokine receptor gamma chain double mutants--requiring exogenous cytokine administration for human hematopoietic stem cell engraftment. J Interferon Cytokine Res. 1999 May;19(5):533-41. PubMed.
  2. Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J, Kim KW, Klein E, Kalchenko V, Bendel P, Lira SA, Jung S, Schwartz M. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity. 2013 Mar 21;38(3):555-69. Epub 2013 Mar 7 PubMed.
  3. Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, Schwartz M. IFN-γ-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013 Nov;136(Pt 11):3427-40. Epub 2013 Oct 1 PubMed.
  4. Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, Mirlas-Neisberg N, Cardon M, Vaknin I, Cahalon L, Berkutzki T, Mattson MP, Gomez-Pinilla F, Friedman N, Schwartz M. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2264-9. Epub 2013 Jan 18 PubMed.
  5. Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012 Sep;12(9):623-35. Epub 2012 Aug 20 PubMed.
  6. Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J Neuroimmunol. 2002 Mar;124(1-2):83-92. PubMed.

Other Citations

  1. APPPS1 

External Citations

  1. Alzheimer’s Genome Project

Further Reading

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