Release of inflammatory cytokines implicated in Alzheimer’s disease requires signaling through inflammasomes. What regulates these innate immune complexes? A June 30 Nature Immunology paper highlights the essential role of CD36, an Aβ-binding scavenger receptor expressed on microglia. Challenging the assumption that inflammasomes rev up in response to extracellular amyloid, the new study suggests that fibrils assembled within lysosomes activate these complexes. Aβ piles up in the lysosomes after entering microglia via CD36, the research suggests. “Rather than accumulating outside the cell, the ‘danger molecules’ form within the macrophage itself,” said senior author Kathryn Moore at New York University School of Medicine. The study, which focused initially on inflammasome activation in atherosclerosis, identifies CD36 as a central regulator of innate immune responses that drive pathogenesis in other inflammatory diseases, including AD and type 2 diabetes, a risk factor for Alzheimer's.

Research implicates interleukin-1β (IL-1β) in many inflammatory disorders. AD, type 2 diabetes, and atherosclerosis each feature build up of insoluble material at sites of inflammation, be it Aβ plaques, amyloid-containing amylin-islet amyloid polypeptide (IAPP), or cholesterol crystals. The prevailing view holds that microglia “get frustrated” trying to engulf these extracellular aggregates and, in turn, trigger NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes to turn on caspases that promote IL-1β secretion. In AD, support for that theory comes from reports of fibrillar amyloid activating NLRP3 in cultured mouse microglial cells (see Halle et al., 2008 ). Moreover, silencing this molecular complex improved cognition and reduced brain Aβ deposition in APP/PS1 mice (ARF related news story), stimulating further interest in the molecular signals that set off the inflammasome.

In their atherosclerosis experiments, lead author Frederick Sheedy and colleagues saw that extracellular aggregates seemed unnecessary for activation of the inflammasome. They were able to activate NLRP3 in vitro by culturing macrophages with soluble precursors to cholesterol aggregates. Within hours, the macrophages took up these precursors (oxidized lipoproteins) and formed cholesterol crystals within lysosomes, as revealed by confocal microscopy. This paralleled intracellular build-up of IL-1β and required CD36, since macrophages lacking this receptor did not form crystals or make IL-1β. Strengthening the in-vitro data, inflammasome activity tanked in CD36-deficient mice and in animals treated with CD36 oligonucleotides that block expression of the gene.

Given that CD36 binds soluble Aβ in vitro (Wilkinson et al., 2011), and mediates microglial and macrophage responses to Aβ in mice (see El Khoury et al., 2003; ARF related news story), the scientists wondered if NLRP3 activation in AD occurs by a similar mechanism.

To test that possibility, the researchers monitored fibril formation and IL-1β release by primary mouse macrophages cultured with soluble synthetic Aβ1-42. Within three hours, thioflavin-S-positive amyloid formed within lysosomes, and IL-1β secretion rose as well. These effects did not show up in macrophages treated with a nonamyloidogenic control peptide, or in cells isolated from CD36 knockout mice. Interestingly, the researchers could prevent IL-1β release by pre-loading lysosomes with Congo red to block fibril formation. The data suggests that NLRP3 inflammasome activation and IL-1β production requires fibrillization of soluble amyloid internalized via CD36, and fits with prior work suggesting that amyloid fibrils form intracellularly (see Friedrich et al., 2010; Walsh et al., 2000; Haass et al., 1992). In addition, the scientists showed that inflammasome activation by IAPP occurs in vitro by a similar mechanism.

Frank Heppner of Charité–Universitätsmedizin Berlin, Germany, found the work “important and encouraging.” It fleshes out an innate immune mechanism to curb amyloidosis by identifying CD36 as a key upstream regulator of NLRP3 activation in three major diseases, he wrote in an email to Alzforum (see full comment below).

Others said that while the findings point to CD36 as a therapeutic target in atherosclerosis, the implications for AD seem less clear. For example, “one would not wish to hinder Aβ clearance by microglia,” Richard Ransohoff of Cleveland Clinic, Ohio, wrote in an email to Alzforum. “On the other hand, if [the CD36 pathway] leads to microglial dysfunction, targeting intracellular events downstream of CD36 might attenuate that while allowing for Abeta clearance and other effector and surveillance functions.”

Moore said ongoing analyses in CD36-deficient AD transgenic mice should help discern the effects of CD36 on inflammasome activity and pathogenesis in vivo.—Esther Landhuis


  1. The identification of CD36 as a key upstream regulator of NLRP3 activation by endogenous, potentially dangerous ligands in three major diseases—namely atherosclerosis, Alzheimer’s disease (AD), and type 2 diabetes—is an important and encouraging finding for many reasons. It elucidates an important innate immune mechanism to contain amyloidosis. Due to the fact that CD36 does not compromise the inflammasome activity required for host defense against pathogens, it provides an attractive and smart target for therapeutic intervention in amyloid-prone diseases. The work also highlights the potential of modulating innate immunity in proteopathic (brain) diseases by identifying CD36 as the common molecular event, even though the initiating pathology in these diseases may differ considerably.

    While CD36 is already known to mediate microglial and macrophage responses to Aβ, implying that it plays a key role in the proinflammatory events associated with AD (El Khoury et al., 2013), the finding by Sheedy et al. suggests it may be feasible to therapeutically target NALP3 in AD (Heneka et al., 2013).

    However, it was also shown that the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone induced Aβ clearance in AD mice by stimulating microglial Aβ phagocytosis in a CD36-mediated manner (Yamanaka et al., 2013).

    Therefore, downregulating CD36 may not only reduce inflammation but may also diminish clearance of Aβ. In this context, the finding by Hickman et al., 2008 describing a substantial decrease in expression of the Aβ-binding scavenger receptors scavenger receptor A, CD36, and RAGE in microglia from old Aβ-laden PS1-APP mice, as well as the increase in microglial CD36 expression in NLRP3-deficient AD mice (Heneka et al.) need to be considered. It will be important to assess AD pathology beyond in-vitro assays in a preclinical in-vivo setting using AD mouse models crossed to CD36-deficient mice. This will also allow us to examine whether not only peripheral macrophages, but also intrinsic microglial functions are changed in the experimental paradigms presented by Moore and colleagues.


    . CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003 Jun 16;197(12):1657-66. PubMed.

    . NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.

    . Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008 Aug 13;28(33):8354-60. PubMed.

    . PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci. 2012 Nov 28;32(48):17321-31. PubMed.

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News Citations

  1. Microglia and AD—Does the Inflammasome Drive Aβ Pathology?
  2. Bad Blood—Scavenger Receptor Links Aβ to Oxidative Stress in Mice

Paper Citations

  1. . The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008 Aug;9(8):857-65. PubMed.
  2. . A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36. J Biol Chem. 2011 Oct 7;286(40):34914-22. PubMed.
  3. . CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003 Jun 16;197(12):1657-66. PubMed.
  4. . Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1942-7. PubMed.
  5. . The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry. 2000 Sep 5;39(35):10831-9. PubMed.
  6. . Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature. 1992 Jun 11;357(6378):500-3. PubMed.

Further Reading

Primary Papers

  1. . CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013 Aug;14(8):812-20. PubMed.