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Review
. 2023 Jul;43(7):1027-1041.
doi: 10.1177/0271678X231170041. Epub 2023 Apr 12.

CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer's disease

Zhengrong Zhang  1 , Qini Gan  1 , Jingyan Han  2 , Qiushan Tao  1 , Wei Qiao Qiu  1   3   4 , Joseph A Madri  5
Affiliations
Review

CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer's disease

Zhengrong Zhang et al. J Cereb Blood Flow Metab. 2023 Jul.

Abstract

Several studies have shown that an abnormal vascular-immunity link could increase Alzheimer's disease (AD) risk; however, the mechanism is unclear. CD31, also named platelet endothelial cell adhesion molecule (PECAM), is a surface membrane protein of both endothelial and immune cells and plays important roles in the interaction between the vascular and immune systems. In this review, we focus on research regarding CD31 biological actions in the pathological process that may contribute to AD based on the following rationales. First, endothelial, leukocyte and soluble forms of CD31 play multi-roles in regulating transendothelial migration, increasing blood-brain barrier (BBB) permeability and resulting in neuroinflammation. Second, CD31 expressed by endothelial and immune cells dynamically modulates numbers of signaling pathways, including Src family kinases, selected G proteins, and β-catenin which in turn affect cell-matrix and cell-cell attachment, activation, permeability, survival, and ultimately neuronal cell injury. In endothelia and immune cells, these diverse CD31-mediated pathways act as a critical regulator in the immunity-endothelia-brain axis, thereby mediating AD pathogenesis in ApoE4 carriers, which is the major genetic risk factor for AD. This evidence suggests a novel mechanism and potential drug target for CD31 in the background of genetic vulnerabilities and peripheral inflammation for AD development and progression.

Keywords: Alzheimer's disease (AD); CD31; blood–brain barrier (BBB); neuroinflammation; trans-endothelia.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Endothelial cell–cell junctions: the relationship of CD31 to tight and adherens junctions (adapted from Engelhardt and Sorokin, Seminars in Immunopathology, 2009). While CD31 (PECAM-1) is in close proximity to both adherents and tight junctional complexes, as is CD99, both molecules are outside of these two organized structures. Studies have shown that CD31 may function as a modulator of VE-cadherin and adherens and tight junction formation as well as endothelial cell survival, proliferation and apoptosis. In addition, CD31 expression has been shown to be modulated by CD44, and CD31 expression, localization and phosphorylation can be affected by the dynamics of adherens and tight junctions.
Figure 2.
Figure 2.
Schematic of the structure and selected binding properties of CD31 (PECAM-1) (adapted from Ilan & Madri, Curr Opin Cell Biol, 2003; Newman & Newman, Arterioscler Thromb Vasc Biol, 2003 & Lertkiatmongkol et al., Curr Opin Hematol, 2016). The molecules found to bind to CD31 (β-catenin, γ-catenin, SHP-2 and STAT3 & STAT-5) are denoted in bold blue type. The CD31 truncations and the site-directed mutations listed were utilized to determine the binding specificities of the binding molecules noted. CD31 functions as a dynamic modulator of cellular behaviors driven in part by differential Y & S phosphorylation, regulating downstream signaling cascades to affect several biological processes, including vasculogenesis, angiogenesis, megakaryocytopoiesis, osteoclastogenesis, permeability and modulation of gene expression (MMP-2, tissue factor and thrombosis) and endothelial cell (migration and cushion formation) and PMN migration. The phosphorylation of Y663 and Y686 mediates the binding and activation of SHP-2 and increases c-src binding. Together, these residues mediate an increase in c-src binding and modulate the protein tyrosine phosphatase SHP-2 binding and activation. The phosphorylation of S673 mediates a decrease in γ-catenin and could also affect SHP-2 binding and its kinetics. When β catenin is tyrosine-phosphorylated, its binding affinity to exon 15 is increased. Y701 mediates STAT family member binding, while Y686 mediates STAT family member Y phosphorylation; PECAM-1 has also been shown to modulate Rho activation via Gai2 binding, affecting single-cell mobility and directed migration.
Figure 3.
Figure 3.
CD31 (PECAM-1) is a dynamic modulator of the cellular behaviors of endothelia and immune cells. CD31 (PECAM-1) mediates the cellular activities in endothelia and immune cells as illustrated: (1) The binding of SHP-1 & -2 to differentially phosphorylated CD31 (Y663 & Y686) results in distinct binding to CD31 and substrate specificities. CD31/SHP-1 & 2 interactions have been shown to modulate moesin phosphorylation, affecting the directed migration of neutrophils and megakaryocytes; the tyrosine phosphorylation state of β-catenin and FAK, vascular permeability, proliferation, apoptosis, gene expression and migration; the activation state of ERK1/2, affecting STAT phosphorylation and cytokine responsiveness; and the tyrosine phosphorylation state of STAT3, affecting cytokine induction. (2) The dynamic interactions of CD31 with CD44 and VE-cadherin decrease the levels of CD31 and are associated with the loss of adherens and tight junction integrity, altering the levels of YAP and survivin and resulting in decreased endothelial apoptosis. (3) CD31 on the surface of endothelial cells modulates the expression of MMP-2 and MMP-9 via induction and nuclear targeting of GATA2 and p53 transcription factors. (4) CD31 interacts with Gαi2, affecting Rho activation, cell motility and migration. (5) CD31's interactions with PI3K modulate Akt activity, which in turn regulates Egr-1 expression via p38 activation, leading to blunting of tissue factor induction, as well as MMP-14 and PAI-1 induction, reducing thrombosis, permeability and apoptosis in endothelial cells. (6) CD31/PI3K interactions also regulate GSK-3β activity via Akt phosphorylation, resulting in blunting of β-catenin serine phosphorylation and reducing its proteosomal degradation. Tyrosine phosphorylated β-catenin binding to CD31 results in sequestration of β-catenin, rendering it incapable of binding to VE-cadherin, affecting junction formation; the binding of γ-catenin to exon 13 of CD31 is dependent upon CD31 residue S673. Effects of CD31 phosphorylation (#1 & 6, Y663, 686, 701, S673) and CD31 expression levels (#2, 3, 4 & 5).
Figure 4.
Figure 4.
Map of CD31 involvement in pathological/protective molecular mechanisms in AD development. As a leukocyte- and vascular cell-specific surface molecule, CD31 is a probable gate-keeping receptor in the inflammatory blood–brain axis. It has been shown to be involved in risk pathways for AD, including transendothelial migration of leukocytes, integrin regulation, T-cell function and competitive binding of ApoE vs. mCRP to the CD31 receptor in regulating the permeability of the BBB and inducing neuroinflammation and neurodegeneration in the brain. Additionally, CD31 mediates anti-AD signaling pathways by suppressing apoptosis and the function of platelets to accelerate the restoration of the BBB. CD31 agonists have the potential to inhibit Scr kinase in the mCRP induced detrimental process, and then by accelerating the resolution of the inflammatory phase to maintain the BBB homeostasis process.
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