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
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Research Models Citations
- García-García E, Rosales C. Signal transduction during Fc receptor-mediated phagocytosis. J Leukoc Biol. 2002 Dec;72(6):1092-108. PubMed.
- Could Neutrophils Be the Newest Players in Neurodegenerative Disease?
- Dementia à la Mold? Fungi May Lurk in Alzheimer’s Brains
- To Be Hale and Hearty, Brain Microglia Need a Healthy Gut
- Systemic Inflammation: A Driver of Neurodegenerative Disease?
- Blessing or Curse? Peripheral Cytokines in the Brain
- Inflammatory Crosstalk Between Periphery and Brain
- 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.