Complement Receptor Found to Regulate Adult Neurogenesis

You may know it for its role in rallying immune cells, but complement receptor also resides on the surface of neural progenitor cells and helps tone down adult hippocampal neurogenesis. This is the upshot of a report in the March 16 Journal of Neuroscience. Researchers led by Tony Wyss-Coray of Stanford University School of Medicine, Palo Alto, California, analyzed complement-receptor knockout mice and found their neurogenesis was up three- to fourfold relative to age-matched wild-type mice. The complement receptor gene CR1 is an AD risk gene, currently occupying place 6 on the AlzGene Top Results ranking.

“That is very novel and interesting, and has major implications for brain injury and neurodegenerative disease—certainly Alzheimer’s,” said Orly Lazarov of the University of Illinois at Chicago in an interview with ARF. The researchers knocked out Cr2, and, hence, Cr1 as well, since both are splice variants of the same gene in mice (Molina et al., 1996). Whether the increased neurogenesis in Cr2-deficient mice has an impact on learning and memory remains to be seen.

The complement inflammatory cascade is a key arm of the innate immune response. It springs into action in the central nervous system during brain injury and neurodegeneration (for reviews, see D’Ambrosio et al., 2001 and Gasque, 2004). Wyss-Coray’s group showed that brain-targeted expression of a complement inhibitor exacerbates Aβ deposition in J20 AD mice that overexpress mutant amyloid precursor protein (APP) (Wyss-Coray et al., 2002), and others reported similar findings after knocking out the central complement protein C3 in the same AD model (ARF related news story on Maier et al., 2008). In line with these analyses, blocking the receptor of a downstream complement component (C5a) alleviates pathology and cognitive decline in Tg2576 and triple transgenic AD mice (see ARF related news story on Fonseca et al., 2009).

Lead author Maiko Moriyama and colleagues wondered what would happen in mice lacking complement receptors. They obtained Cr2 knockouts and mice lacking Cr3, a phagocyte receptor restricted to brain microglia and macrophages (Coxon et al., 1996). The researchers also generated a transgenic strain expressing an enhanced green fluorescent protein (EGFP) reporter under the control of the Cr2 promoter. Confocal microscopy revealed EGFP expression in neural progenitors of the dentate gyrus. They followed with immunofluorescence studies in Cr2-deficient mice, looking at expression of the neuroblast proliferation marker doublecortin (Dcx) in the dentate gyrus. Compared with age-matched wild-type controls, Cr2 knockouts had double the number of Dcx+ cells at eight weeks and five to seven months of age, and a nearly threefold increase by 13-16 months. In contrast, Cr3-deficient mice expressed Dcx on dentate granule cells at levels comparable to that of wild-type controls.

The overabundant Dcx-expressing cells in Cr2-deficient mice did not arise because of increased proliferation overall. In a short-term labeling study, Cr2-/- mice injected for six days with the nucleotide analog bromodeoxyuridine (BrdU) had comparable total numbers of BrdU-positive dentate granule cells as did wild-type animals. However, more of those newly dividing cells turned into NeuN-positive neuronal cells, at the expense of GFAP-expressing glial cells. “This suggests that if you remove the signal delivered through Cr2, you favor the neuronal lineage,” Wyss-Coray said. “We interpret this to mean there is an endogenous tonic inhibition of Cr2, and that keeps a balance between glial and neuronal cells. If you remove the receptor, you lift the inhibition and make more neurons.”

As further support for Cr2’s role in neurogenesis, the researchers showed they could curb proliferation of wild-type mouse hippocampal neuroblasts by treating them in culture with human C3d, a functional ligand for mouse Cr2. C3d-neutralizing antibody wiped out the effect, as did use of Cr2-deficient neural progenitors. The team achieved a similar neurogenesis slowdown by exposing the neuroblasts to interferon-α (IFNα)—a proinflammatory cytokine that binds Cr2 at the same site as does C3d, and with comparable affinity. Consistent with the cell culture data, injecting C3d into the right dentate gyrus of wild-type mice reduced the number of proliferating Dcx-positive cells by 35 percent, relative to the saline-injected left side, but had no effect on Cr2 knockout mice.

The functional significance of these findings are unclear at present. If adult-born neurons are “indeed involved in formation of new memories, then you would expect Cr2-deficient mice to be smarter, or have better capacity to learn something new,” Wyss-Coray told ARF. “That’s a question we have to answer.” Also in the works are studies to test if driving neurogenesis by blocking Cr2 can improve cognition in AD models, Wyss-Coray said.

There is evidence from rodent studies that freshly generated adult neurons do matter for cognition, and possibly for AD. Exercise helps older mice sprout new neurons and perform better in spatial memory tests (ARF related news story on van Praag et al., 2005). And in a recent paper (Hu et al., 2010), Lazarov and colleagues reported that environmental enrichment not only spurred neurogenesis, but also boosted synaptic plasticity, and, in keeping with their earlier work (see ARF related news story on Lazarov et al., 2005), reduced Aβ pathology in an AD mouse model. That study did not assess cognition, but earlier research on that same AD strain (APPswe/PS1ΔE9) showed enrichment-induced improvements in spatial learning (Jankowsky et al., 2005), albeit with an increase in Aβ pathology (see Jankowsky et al., 2003). On the flip side, shutting down neurogenesis has been shown to block environment-triggered memory enhancement in rats (Bruel-Jungerman et al., 2005).

However, the situation is complicated. Scientists have found that neurogenesis may not be required for environmental enrichment effects (see ARF related news story on Meshi et al., 2006), and that in some cases, enrichment does not rescue neurogenesis in AD mice (see ARF comment on Demars et al., 2010 and Wang et al., 2010).

A paper published online March 14 in the Proceedings of the National Academy of Sciences offers yet another twist. Researchers led by Geoffrey Murphy, University of Michigan Medical School, Ann Arbor, report that “prolonged suppression of neurogenesis in young-adult mice results in wide-ranging compensatory changes in the structure and dynamics of the dentate gyrus that function to restore plasticity.” Wiping out neurogenesis impaired dentate gyrus long-term potentiation (LTP), but only for a limited time. Within six weeks, LTP was restored, and this restoration occurred in the absence of neurogenesis (Singer et al., 2011).

For the time being, Wyss-Coray’s findings seem to offer “another molecular link in a growing list of molecular links between adult neurogenesis and AD,” Lazarov told ARF. She and her colleagues proposed another potential link in a February 16 Journal of Neuroscience paper. That study suggests that PS1 knockdown drives early differentiation of neural progenitor cells, accompanied by a reduction in cell proliferation (Gadadhar et al., 2011).

The Cr2 findings may also give researchers a handle on the link between AD and the CR1 locus, which turned up in recent genomewide association studies (see ARF related news story on Lambert et al., 2009; ARF related news story on Carrasquillo et al., 2010; Corneveaux et al., 2010). Based on published studies, it is unclear at this point which polymorphisms in the CR1 locus have functional consequences and what those might be, Wyss-Coray noted. Furthermore, since Cr1 and Cr2 are encoded on the same gene in mice, it is possible that Cr1 had some role in the neurogenesis effects seen in the Cr2 knockouts.—Esther Landhuis

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References

News Citations

  1. Complement: AD Friend or Foe? New Work Tips Balance to Former
  2. AD Therapeutic Approaches Tap Complement, Mitochondrial Antioxidant
  3. Exercise Helps Mouse Elders Learn, Generate New Neurons
  4. Sorrento: More Fun, Less Amyloid for Transgenic Mice
  5. Neurogenesis Not Needed for Environmental Enrichment Effects
  6. Early Casualty, Neurogenesis Cripples Cognition in AD Mice
  7. Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published
  8. Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies

Paper Citations

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Other Citations

  1. J20 AD mice

External Citations

  1. CR1 locus

Further Reading

Primary Papers

  1. Moriyama M, Fukuhara T, Britschgi M, He Y, Narasimhan R, Villeda S, Molina H, Huber BT, Holers M, Wyss-Coray T. Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis. J Neurosci. 2011 Mar 16;31(11):3981-9. PubMed.

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