31 May 2024

Sometimes being polite does more harm than good. When glia surround amyloid plaques, they keep their distance from one another in structured cellular nets. These manners are enforced by the axon guidance receptor Plexin-B1, according to a paper published May 27 in Nature Neuroscience. Scientists led by Bin Zhang, Hongyan Zou, and Roland Friedel at New York’s Icahn School of Medicine at Mount Sinai reported that deleting Plexin-B1 in a mouse model of amyloidosis freed astrocytes and microglia to huddle closer around plaques. This led to smaller, denser aggregates that posed less of a threat to nearby synapses. Unfettering the cells of their social graces also dampened neuroinflammation and lessened memory loss in the mice.

The authors, and other scientists, had previously tied elevated Plexin-B1 expression in postmortem brain samples to cognitive decline and AD (Wang et al., 2018; Jun 2018 news). However, how this association might work remained obscure. Plexin-B1 binds semaphorin ligands, including Sema4D. They sit on the surface of multiple neural cell types, but can also be secreted. These receptor-ligand pairs guide axon growth during development, and have also been found to repel cells from one another, presumably giving them enough “personal space” to get on with their jobs (Roy et al., 2017; Zhou et al., 2020). 

To investigate if Plexin-B1 influences AD pathogenesis, co-first authors Yong Huang and Minghui Wang first asked which cell types make the receptor. Their previous work suggested astrocytes were the main source, and a deeper analysis of data from Mount Sinai’s Brain Bank AD cohort showed that indeed, expression of Plexin-B1 in astrocytes, but not other cell types, correlated with plaque burden. Immunohistochemistry of AD brain tissue revealed plaques encircled by a prominent corona of Plexin B1, consistent with the shape of a glial net (image at right), while expression was weak far from plaques. Notably, among samples from 11 people who spanned the spectrum of AD, Plexin-B1 expression surrounding plaques was highest among those with the heaviest overall burden of AD pathology based on amyloid plaques, neuritic plaques, and neurofibrillary tangles. In APP/PS1 mice, plaque-adjacent astrocytes, but not microglia, expressed the receptor.

To find out if the Plexin-B1 around plaques plays any role in pathology, the researchers knocked out the receptor from APP/PS1 mice. The results were striking. In 6-month-old APP/PS1 control mice, astrocytes formed spheres around plaques that were about two cell layers wide. In mice lacking Plexin-B1, the footprint of this net cinched by more than half. It contained fewer astrocytes, but closer together, and more of them directly probed the plaque surface with their processes. Microglia responded similarly, moving closer to each other and to plaques, though again with fewer cells recruited overall.

Tightening Net. In APP/PS1 mice (left), astrocytes (green), and microglia (light grey) encircle an Aβ plaque (red) in a loose net. In Plexin-B1 knockouts (right), the net tightens, and glia directly engage the plaque surface. [Courtesy of Huang et al., Nature Neuroscience, 2024.]

Why the packed net? Single-cell RNA sequencing revealed nine subclusters of astrocytes, including one with a reactive, disease-associated astrocyte (DAA) signature. In APP/PS1 controls, these cells expressed most of the Plexin-B1, and the scientists think these are the astrocytes surrounding plaques. Without Plexin-B1, this cluster shrank, and the cells expressed higher levels of genes involved in forming cell projections and bolstering energy metabolism. Plexin-B1 deletion also reduced numbers of disease-associated microglia (DAM), while boosting their expression of genes involved in microglial activation, chemoattraction, host defense, and antigen presentation. In all, the findings hinted at a scaled-down, yet more potent, response to plaques among microglia and astrocytes. Notably, communication between the two cell types seemed to improve, as expression of both ligands and receptors involved in cell-to-cell signaling surged.

Huddle Up! In APP/PS1 controls (left), astrocytes (green) and microglia (brown) form a wide glial net around plaques. Without Plexin-B1 to enforce cell spacing (right), glia crowd together and around plaques, compacting them more. [Courtesy of Huang et al., Nature Neuroscience, 2024.]

This potency manifested in the plaque load. Without Plexin-B1, average plaque size shrank by almost half. They also became denser. In APP/PS1 controls, half of the plaques were diffuse, 15 percent had dense cores, and the rest were of mixed composition. The opposite was true in Plexin-B1 knockouts, where half of the plaques had dense cores, and 15 percent were purely diffuse. This greater compaction spared nearby synapses, as seen by a 50 percent reduction in dystrophic neurites. Finally, this translated into better working memory for the mice, which more readily learned the location of an escape hatch on a circular platform relative to their Plexin-B1-replete counterparts.

The shift toward more dense-core plaques jibes with previous studies implicating microglia as plaque compactors (Apr 2021 news; May 2016 news). With microglia better able to do this, fewer glia need to be recruited to the scene, leading to fewer cells surrounding plaques and less neuroinflammation.

Zhang told Alzforum that details about the signaling pathway need to be worked out. Greg Lemke of the Salk Institute in La Jolla, California, agrees, but found the study interesting. “Important features of signaling within the glial nets—e.g., the identity of the Plexin-B1 ligand, how Plexin-B1 activation in astrocytes affects the physiology of microglia—remain to be determined,” he wrote. “Nonetheless, pharmacological perturbation of Plexin-B1 signaling could be experimentally assessed as an AD therapy.”

A recent study suggests that microglia expressing Sema4D can activate Plexin-B1 on astrocytes (Clark et al., 2021). Indeed, some Plexin-B1 ligands—the semaphorins—are already being targeted in clinical trials. For example, a Sema4D-targeted antibody, pepinemab, is being tested in clinical trials for AD, based in part on observations that neurons upregulate Sema4D in AD (Evans et al., 2022). A Sema4D-blocking nanobody, as well as a Plexin-B1-binding peptide, has also been developed (Cowan et al., 2023; Matsunaga et al., 2016).—Jessica Shugart

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References

News Citations

1. Culling Connection From Chaos, Alzheimer’s Genetic Network Study Pins PLXNB1 and INPPL1 1 Jun 2018
2. Microglia Build Plaques to Protect the Brain 21 Apr 2021
3. Barrier Function: TREM2 Helps Microglia to Compact Amyloid Plaques 28 May 2016

Therapeutics Citations

1. Pepinemab

Paper Citations

1. Wang M, Beckmann ND, Roussos P, Wang E, Zhou X, Wang Q, Ming C, Neff R, Ma W, Fullard JF, Hauberg ME, Bendl J, Peters MA, Logsdon B, Wang P, Mahajan M, Mangravite LM, Dammer EB, Duong DM, Lah JJ, Seyfried NT, Levey AI, Buxbaum JD, Ehrlich M, Gandy S, Katsel P, Haroutunian V, Schadt E, Zhang B. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease. Sci Data. 2018 Sep 11;5:180185. PubMed.
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4. Clark IC, Gutiérrez-Vázquez C, Wheeler MA, Li Z, Rothhammer V, Linnerbauer M, Sanmarco LM, Guo L, Blain M, Zandee SE, Chao CC, Batterman KV, Schwabenland M, Lotfy P, Tejeda-Velarde A, Hewson P, Manganeli Polonio C, Shultis MW, Salem Y, Tjon EC, Fonseca-Castro PH, Borucki DM, Alves de Lima K, Plasencia A, Abate AR, Rosene DL, Hodgetts KJ, Prinz M, Antel JP, Prat A, Quintana FJ. Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science. 2021 Apr 23;372(6540) PubMed.
5. Evans EE, Mishra V, Mallow C, Gersz EM, Balch L, Howell A, Reilly C, Smith ES, Fisher TL, Zauderer M. Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity. J Neuroinflammation. 2022 Aug 6;19(1):200. PubMed.
6. Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G. Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signaling. J Biol Chem. 2023 Jun;299(6):104740. Epub 2023 Apr 23 PubMed.
7. Matsunaga Y, Bashiruddin NK, Kitago Y, Takagi J, Suga H. Allosteric Inhibition of a Semaphorin 4D Receptor Plexin B1 by a High-Affinity Macrocyclic Peptide. Cell Chem Biol. 2016 Nov 17;23(11):1341-1350. Epub 2016 Oct 27 PubMed.

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