Huang Y, Wang M, Ni H, Zhang J, Li A, Hu B, Junqueira Alves C, Wahane S, Rios de Anda M, Ho L, Li Y, Kang S, Neff R, Kostic A, Buxbaum JD, Crary JF, Brennand KJ, Zhang B, Zou H, Friedel RH. Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer's disease. Nat Neurosci. 2024 Aug;27(8):1489-1504. Epub 2024 May 27 PubMed.
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Salk Institute
This interesting study provides evidence that the class 4 semaphorin receptor Plexin-B1, which is prominently expressed by the astrocytes that surround amyloid beta plaques in Alzheimer’s disease, regulates both astrocyte spacing around, and microglia association with, these plaques.
When germline Plexin-B1 mouse mutants are crossed into the APP/PS1 AD model, microglia and peripheral astrocytes are seen to associate much more tightly with Aβ plaques, and the cytoarchitecture of these plaques is seen to shift from a wispy fibrillar (more neurotoxic) to a compacted dense-core (less neurotoxic) configuration.
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. Nonetheless, pharmacological perturbation of Plexin-B1 signaling—not addressed in this study—could be experimentally assessed as an AD therapy.
View all comments by Greg LemkeVaccinex, Inc.
As noted in this interesting article, we are testing a Sema4D-targeted antibody, pepinemab, in an early stage randomized, Phase 1b/2 clinical trial for AD. SEMA4D is a major ligand for activation of plexin-B1; it is, therefore, of considerable interest to compare the effects of anti-SEMA4D antibody blockade with those reported by the present authors for plexin-B1 KO.
The effect of plexin-B1 KO on the glial net surrounding amyloid plaques, including interactions among astrocytes and between astrocytes and microglia, is certainly interesting and, as suggested by the authors, may contribute to relieving AD pathology. An important property of astrocytes is their distribution in tiled fashion such that individual astrocytes establish a local sphere of influence in which surveillance is enabled through numerous branching projections. Remarkably, a single human astrocyte may in this fashion make hundreds of thousands of cell contacts. This contrasts with the mobile surveillance strategy adopted by less numerous microglia and implies a mechanism for mutual repulsion by astrocytes. Results of the present report suggest that plexin-B1 and an unidentified ligand, possibly SEMA4D, may serve this purpose. The same, or similar, ligand-receptor signaling pairs may also mediate crosstalk between astrocytes and microglia as previously suggested by Clark et al., 2021, who identified SEMA4D as a relevant ligand.
It is, however, important to note that these are not the only astrocyte interactions mediated by these, and potentially related, ligand-receptor signaling pairs, e.g. plexin-B2 and other class IV semaphorins. We have reported that SEMA4D is highly upregulated in neurons during progression of AD and Huntington’s disease (HD), and that this facilitates signaling between neurons and closely associated plexin-B1 positive astrocytes which, in their homeostatic state, are responsible for recycling glutamate at synapses, support energy metabolism, and maintain ionic gradients (Evans et al., 2022). This SEMA4D-plexin-B1 interaction appears to trigger reactive astrogliosis, including loss of supportive functions and gain of neuroinflammatory activity. We have reported beneficial effects of treatment with SEMA4D blocking antibody in HD (Feigin et al., 2022) and plan to shortly report topline data for the SIGNAL-AD randomized, Phase 1b/2 study in AD.
Unfortunately, for what appear to be technical reasons, neither Huang et al., 2024, nor Clark et al., 2021, were able to characterize astrocyte interactions with neurons. Zhang at al. comment that “attempts for additional detection of Plexin-B1 in human brain specimens by RNAscope ISH or IF were not successful, likely due to preservation challenges for postmortem tissues,” and "due to technical factors related to tissue dissociation, neurons were underrepresented in this analysis.” As noted, peri-plaque astrocytes are a minority population compared to the general astrocyte populations in plaque-free areas. We wish to highlight that these other, more numerous, astrocyte populations can contribute to neuroinflammation and neurodegeneration in different ways. Indeed, the interesting thing about targeting central regulators of glial physiology, like plexin-B1 and SEMA4D, is that their effects are pleiotropic.
References:
Huang Y, Wang M, Ni H, Zhang J, Li A, Hu B, Junqueira Alves C, Wahane S, Rios de Anda M, Ho L, Li Y, Kang S, Neff R, Kostic A, Buxbaum JD, Crary JF, Brennand KJ, Zhang B, Zou H, Friedel RH. Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer's disease. Nat Neurosci. 2024 Aug;27(8):1489-1504. Epub 2024 May 27 PubMed.
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.
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.
Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, Mishra V, Manber R, Walters KA, Kowarski L, Oakes D, Siemers E, Kieburtz KD, Zauderer M, Huntington Study Group SIGNAL investigators. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med. 2022 Oct;28(10):2183-2193. Epub 2022 Aug 8 PubMed. Correction.
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