Monomeric C‐reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype‐dependent pattern: A risk factor for Alzheimer’s disease?

Zhang, Zhengrong; Na, Hana; Gan, Qini; Qin, Tao; Alekseyev, Yuriy O.; Hu, Junming; Yan, Zili; Jb, Yang; Tian, Hua; Zhu, Shenyu; Li, Qiang; Rajab, Ibraheem M.; Blusztajn, J. K.; Wolozin, Benjamin; Emili, Andrew; Zhang, Xiaoling; Stein, Thor D.; Potempa, Lawrence A.; Qiu, Wei Qiao

doi:10.1111/acel.13501

Cited by 32 publications

(38 citation statements)

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“…Other studies suggest a pathological role for mCRP in atherosclerosis, thrombosis, angiogenesis, and cerebrovascular pathologies ( 96 , 97 ). mCRP antigen has been found in brain tissues associated with damaged micro vessels and in human and mouse brains involved with neuroinflammation ( 98 – 100 ). Since mCRP forms from pCRP, drugs that inhibit the in situ formation of mCRP from pCRP could have therapeutic value in treating both systemic and cerebral inflammatory diseases ( 3 , 101 ).…”

Section: Clinical Relevance Of C-reactive Protein-lipoprotein Interac...mentioning

confidence: 99%

“…A relationship between apo E4 and plasma CRP levels relevant to the development of Alzheimer’s disease has been reported ( 104 ). Furthermore, the mCRP isoform bound to endothelial cell CD31 (a receptor mediating platelet and leukocyte binding and transcytosis), influencing apo E4-related responses in the development of Alzheimer’s disease ( 100 ).…”

Section: Clinical Relevance Of C-reactive Protein-lipoprotein Interac...mentioning

confidence: 99%

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Relevance of lipoproteins, membranes, and extracellular vesicles in understanding C-reactive protein biochemical structure and biological activities

Potempa

Qiu

Stefanski

et al. 2022

Front. Cardiovasc. Med.

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Early purification protocols for C-reactive protein (CRP) often involved co-isolation of lipoproteins, primarily very low-density lipoproteins (VLDLs). The interaction with lipid particles was initially attributed to CRP’s calcium-dependent binding affinity for its primary ligand—phosphocholine—the predominant hydrophilic head group expressed on phospholipids of most lipoprotein particles. Later, CRP was shown to additionally express binding affinity for apolipoprotein B (apo B), a predominant apolipoprotein of both VLDL and LDL particles. Apo B interaction with CRP was shown to be mediated by a cationic peptide sequence in apo B. Optimal apo B binding required CRP to be surface immobilized or aggregated, treatments now known to structurally change CRP from its serum soluble pentamer isoform (i.e., pCRP) into its poorly soluble, modified, monomeric isoform (i.e., mCRP). Other cationic ligands have been described for CRP which affect complement activation, histone bioactivities, and interactions with membranes. mCRP, but not pCRP, binds cholesterol and activates signaling pathways that activate pro-inflammatory bioactivities long associated with CRP as a biomarker. Hence, a key step to express CRP’s biofunctions is its conversion into its mCRP isoform. Conversion occurs when (1) pCRP binds to a membrane surface expressed ligand (often phosphocholine); (2) biochemical forces associated with binding cause relaxation/partial dissociation of secondary and tertiary structures into a swollen membrane bound intermediate (described as mCRPm or pCRP*); (3) further structural relaxation which leads to total, irreversible dissociation of the pentamer into mCRP and expression of a cholesterol/multi-ligand binding sequence that extends into the subunit core; (4) reduction of the CRP subunit intrachain disulfide bond which enhances CRP’s binding accessibility for various ligands and activates acute phase proinflammatory responses. Taken together, the biofunctions of CRP involve both lipid and protein interactions and a conformational rearrangement of higher order structure that affects its role as a mediator of inflammatory responses.

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Section: Clinical Relevance Of C-reactive Protein-lipoprotein Interac...mentioning

confidence: 99%

Section: Clinical Relevance Of C-reactive Protein-lipoprotein Interac...mentioning

confidence: 99%

Relevance of lipoproteins, membranes, and extracellular vesicles in understanding C-reactive protein biochemical structure and biological activities

Potempa

Qiu

Stefanski

et al. 2022

Front. Cardiovasc. Med.

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“…Indeed, our recent research shows that peripheral intraperitoneal injection of mCRP into APOE knock‐in mice induced significant neuroinflammation of astrocytes and microglia in the brain of APOE ε4 mice. 41 On the other hand, the receptor(s) for mCRP's activities in neurons is unknown. However, it is shown that CRP can bind to phosphocholine in cell membrane and bind to FcgammaRI and FcgammaRIIa in immune cells.…”

Section: Discussionmentioning

confidence: 99%

Monomeric C‐reactive protein induces the cellular pathology of Alzheimer's disease

Gan

Wong

Zhang

et al. 2022

A&D Transl Res & Clin Interv

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Introduction Human study shows that elevated C‐reactive protein (CRP) in blood impacts apolipoprotein E ( APOE ) ε4, but not APOE ε3 or APOE ε2, genotype to increase the risk of Alzheimer's disease (AD). However, whether CRP is directly involved in cellular AD pathogenesis and in which type of neuronal cells of APOE ε4 carriers are unknown. Methods We aimed to use different primary neuronal cells and investigate if CRP induces cellular AD pathology depending on APOE genotypes. Here the different primary neuronal cells from the different APOE genotype knock‐in mice cortex were isolated and used. Results Monomeric CRP (mCRP) increased amyloid beta production and, in parallel, induced tau phosphorylation in addition to their related proteins in the primary neurons in a pattern of APOE ε4 > APOE ε3 > APOE ε2 in a dose‐ and time‐dependent manner. Consistently, mCRP induced the staining of other neurodegenerative biomarkers, including Fluoro‐Jade B stain (FjB), TUNEL and Cleaved Caspase‐3, in primary neurons in a similar pattern of APOE ε4 > APOE ε3 > APOE ε2. In contrast, pentameric CRP (pCRP) had a tendency to induce cellular AD pathology but did not reach statistical significance. On the other hand, it is intriguing that regardless of APOE genotype, mCRP did not influence the expressions of Iba‐1 and CD68 in primary microglia or the expression of glial fibrillary acidic protein in primary astrocytes, and additionally mCRP did not affect the secretions of interleukin (IL)‐1α, IL‐1β, and tumor necrosis factor α from these cells. Discussion This is the first report to demonstrate that mCRP directly induces cellular AD pathogenesis in neurons in an APOE genotype‐dependent pattern, suggesting that mCRP plays a role as a mediator involved in the APOE ε4‐related pathway for AD during chronic inflammation. Highlights Pentameric C‐reactive protein (pCRP) can be dissociated irreversibly to form free subunits or monomeric CRP (mCRP) during and after the acute phase. mCRP increased amyloid beta production in the primary neurons in a pattern of apolipoprotein E ( APOE ) ε4 > APOE ε3 > APOE ε2 in a dose‐dependent manner. mCRP induced the expression of phosphorylated tau in the primary neurons in a pattern of APOE ε4 > APOE ε3 > ...

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“…Since then, further investigations have confirmed the ability of mCRP following hippocampal injection in mice, to induce behavioral and memory/cognitive deficits (which was protected against following co-injection of a specific antibody against mCRP) whilst co-localizing with both phosphorylated Tau (p-Tau) and Ab(42); an in vitro capability of mCRP to induce Tau phosphorylation and stimulate production of other AD-precursors including presenilin enhancer protein-2 and phosphorylated amyloid precursor protein (19,20); and from an immunohistochemical study of a cohort of AD post-mortem cases, a strong co-localization of mCRP with inflammatory markers including CD68 (macrophages), nuclear factor kappa B and interleukin-1-beta (IL-1b) (21). Most recently, Zhang et al (22), proposed a mechanism involving mCRP binding and phosphorylation of CD31 on endothelial cells stimulated neuro-inflammation dependent on apolipoprotein E4 postulating this as a pathway leading to increased risk of AD. There is little doubt now that mCRP has an important role in stimulating brain systemic neuro-inflammation and promoting AD pathobiology, whilst a potential role in other brain or CNS/ PNS disorders; including neuropsychological conditions, where mCRP has been recently highlighted as a possible indicator but this has yet to be researched in detail.…”

Section: Evidence Of the Disease Modifying Behavior Of Mcrpmentioning

confidence: 98%

Monomeric C-Reactive Protein: Current Perspectives for Utilization and Inclusion as a Prognostic Indicator and Therapeutic Target

2022

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Monomeric C-reactive protein (mCRP), once thought to be a figment of the imagination and whose biological activity was ascribed to its sodium azide preservative, has now pronounced itself as a critical molecule playing a direct role in mediating many of the acute and chronic aberrant pathological responses to inflammation. In this focused mini review, we describe the currently attributed pathobiological interactions of mCRP in disease, where its tissue and cellular distribution and deposition have recently been clearly characterized and linked to inflammation and other pathway-associated progression of neurological and cardiovascular complications and deleterious outcomes. and focus upon current opinions as to the diagnostic and prognostic potential of mCRP-plasma circulating protein and define the possible future therapeutics including ongoing research attempting to block CRP dissociation with small molecule inhibitors or prevention of cell surface binding directly using antibodies or modified orphan drug targeting directed towards CRP, inhibiting its cellular interactions and signaling activation. There is no doubt that understanding the full influence of the biological power of mCRP in disease development and outcome will be considered a critical parameter in future stratified treatment.

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Monomeric C‐reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype‐dependent pattern: A risk factor for Alzheimer’s disease?

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 32 publications

References 67 publications

Relevance of lipoproteins, membranes, and extracellular vesicles in understanding C-reactive protein biochemical structure and biological activities

Relevance of lipoproteins, membranes, and extracellular vesicles in understanding C-reactive protein biochemical structure and biological activities

Monomeric C‐reactive protein induces the cellular pathology of Alzheimer's disease

Monomeric C-Reactive Protein: Current Perspectives for Utilization and Inclusion as a Prognostic Indicator and Therapeutic Target

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