From their perch on the microglial surface, CD33 and TREM2 exact opposing forces on microglial functions, including phagocytosis and inflammatory responses. Now, in a study published in Neuron on July 10, researchers led by Rudolph Tanzi at Massachusetts General Hospital in Boston draw closer connections between the two AD risk genes. They found that in an AD mouse model, knocking out CD33 boosted microglial phagocytosis and clearance of Aβ plaques, and even prevented memory problems—but not if TREM2 was also deleted. The findings suggest that CD33 acts via TREM2 to tweak microglial function, though exactly how the signaling pathways of the two receptors intersect remains to be ironed out. “[The findings] strongly argue that the microglial signaling pathways that are controlled by CD33 and TREM2 intersect or overlap,” commented David Holtzman of Washington University in St. Louis. "This is an important result in thinking about the implications of targeting these receptors."

  • The AD risk genes CD33 and TREM2 exert opposing influences on microglial function.
  • Deleting CD33 lowers Aβ burden, but only when TREM2 is expressed.
  • Gene expression changes evoked by CD33 knockout depend on TREM2 expression.

Myriad mouse studies implicate TREM2 in microglial recruitment, survival, and in their containment of plaques, while CD33 squelches those processes and riles up pro-inflammatory responses (Griciuc et al., 2013Aug 2013 news). Variants that hobble TREM2 function boost AD risk, while variants that lower CD33 function or expression are protective. Inhibition of CD33 and enhancement of TREM2 signaling are being pursued as potential therapies for AD (Apr 2019 conference news and May 2019 conference news). But do the two microglial receptors affect each other’s function?

First author Ana Griciuc and colleagues addressed this by generating 5xFAD mice that lacked expression of either or both of the microglial receptors. First, they asked how TREM2 would modulate the protective benefits of ditching CD33. While 7-month-old 5xFAD mice had deficits in spatial memory—as gauged by their ability to locate a hidden platform—5xFAD mice lacking CD33 remembered normally. However, animals lacking both CD33 and TREM2 had just as much trouble locating a hidden platform as 5xFAD mice expressing both. Knocking out CD33 also spared cortical neurons in 5xFAD mice, and TREM2 deletion canceled out that protection as well.

TREM2 Required. Knocking out CD33 lowered plaque burden in 5xFAD mice, but not when TREM2 was also deleted. [Courtesy of Griciuc et al., Neuron, 2019.]

The same was true when the researchers measured Aβ deposition. CD33-deficient 5xFAD mice had markedly fewer plaques and lower levels of insoluble Aβ42 than 5xFAD controls, but knocking out TREM2 eliminated this protective effect. In fact, TREM2-deficient 5xFAD mice had an increased plaque load compared to regular 5xFAD animals at 8 months of age, as has been reported before (Feb 2015 news). This negative effect of TREM2 deletion did not waver when CD33 was also knocked out.

Knocking out CD33 did not affect microglial clustering around plaques, suggesting that the cells are able to find plaques just as well as do wild-type microglia. However, deleting TREM2 did reduce clustering around plaques. Double knockout mice had the least microglial clustering, though it is not clear why.

To dig deeper into the connections between TREM2 and CD33, the researchers looked to microglial gene expression profiles. In a nutshell, knocking out CD33 in 5xFAD mice caused an uptick in expression of genes related to phagocytosis, microglial activation, and cytokine production, while knocking out TREM2 downregulated expression of genes involved in these processes. Many of the gene-expression changes evoked by CD33 deletion depended upon expression of TREM2. However, the reverse was not true: The same gene-expression changes occurred in TREM2 knockouts regardless of CD33. The findings jibe with the idea that TREM2 is a critical gatekeeper between homeostatic and disease states (Jul 2018 news).

The researchers have yet to tease out exactly how CD33 and TREM2 signaling interact, but the intracellular social circles of the two receptors clearly overlap. They have a cadre of intracellular adaptors and signaling molecules and pathways in common, even though they bind different extracellular ligands. Most notably, TREM2 signals via the DAP12/Tyrobp adaptor, which binds Syk, leading to activation of PI3K. Conversely, the intracellular portion of CD33 binds SHP1, which blocks activation of PI3K. Tanzi’s lab is investigating how these shared intracellular factors converge to control microglial function. He suggested that in addition to directly blocking CD33 or boosting TREM2, these intracellular signaling molecules, such as Syk, could also make promising therapeutic targets.—Jessica Shugart

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References

News Citations

  1. Protective Microglial Gene Variant Promotes Phagocytosis
  2. Could CD33 Be the Microglial Target for Stimulating Phagocytosis?
  3. Antibodies Against Microglial Receptors TREM2 and CD33 Head to Trials
  4. TREM2 Buoys Microglial Disaster Relief Efforts in AD and Stroke
  5. TREM2: Diehard Microglial Supporter, Consequences Be DAMed

Research Models Citations

  1. 5xFAD (C57BL6)

Paper Citations

  1. . Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013 May 22;78(4):631-43. PubMed.

Further Reading

Papers

  1. . Evaluation of CD33 as a genetic risk factor for Alzheimer's disease. Acta Neuropathol. 2019 Aug;138(2):187-199. Epub 2019 Apr 4 PubMed.

Primary Papers

  1. . TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease. Neuron doi.org/10.1016/j.neuron.2019.06.010