Monomeric CRP (mCRP): A new key player in Alzheimer's Disease?
For decades research on C-reactive protein (CRP) has elucidated its role in innate immunity and inflammatory response. It is an acute phase protein immediately responding to tissue damage by activating the complement system, promoting phagocytosis by macrophages, and stimulating cytokine release. Because CRP is so responsive to inflammation, it’s measurement in blood has been a useful biomarker of infection, chronic inflammation associated with rheumatoid arthritis, Lupis, Crohn’s disease, and heart attack risk.
CRP is not a single structural protein but rather it can undergo a non-proteolytic subunit dissociation which results in a conformational change into at least two structurally and functionally distinctive forms. Potempa et al. summarized the process in a recent review explaining how the hepatocyte-produced pentameric blood soluble and weakly anti-inflammatory protein (pCRP) becomes converted into the monomeric version (mCRP) that is insoluble in the blood and found almost entirely partnered with particulate components, cells and tissues and having significantly higher inflammatory and other bioactive properties.
mCRP and Dementia
CRP expression may be upregulated in glutamate neurons during specific disease states such as Alzheimer’s dementia. Human and animal studies show that mCRP co-localizes with amyloid beta plaques and with phosphorylated tau protein in the hippocampus.
Inflammatory damage spreading from small blood vessels and linked dysregulation of amyloid β metabolism in neurons have been implicated in the origin of Alzheimer disease. It is known that mCRP accumulates in brain micro-vessels after ischemic stroke, where it promotes aberrant angiogenesis, accumulation of amyloid β and probably de novo synthesis of amyloid β (Slevin et al. 2020). Therefore, mCRP might cause both vascular and neuronal degeneration and underlie the processes leading to post-stroke dementia.
Figure 1: Monomeric C-reactive protein (mCRP) is present in significant amounts in the tissue and extracellular matrix of infarcted human post-mortem brain tissue (from the series listed in Al-Baradie et al.: Here, we show (left)-microvascular “pockets” of mCRP (DAB brown; scale bar 200 μm) infiltrating the local cerebral parenchyma (arrows) and (right)-magnified appearance of a leaking cortical microvessel with localized mCRP-positive inflammatory reaction and immune-infiltration (arrow; scale bar 100 μm; DAB brown development).
Further direct evidence of neuropathology caused by mCRP comes from a study by Garcia-Lara et al. (2021). A single administration of mCRP into the hippocampus of mice caused memory loss lasting at least 6 months along with increased hyperphosphorylated tau production. Co-treatment with anti-mCRP resulted in no such effects. Using primary mouse neuronal cultures, Gan et al. (2022) demonstrated that mCRP increased amyloid beta production and, in parallel, induced tau phosphorylation in primary neurons in a time- and dose-dependent manner particularly from APOEε4 carriers. In contrast, pentameric CRP (pCRP) did not induce AD pathology in a statistically significant way.
Specific targeting of mCRP could be a therapeutic approach in conditions such as stroke-affected brains or in APOEε4 carriers in order to halt subsequent neurodegeneration and dementia. The prevalence of dementia in stroke survivors is about 30%, and a high proportion of these patients suffer from Alzheimer disease in addition to those with either vascular or mixed Alzheimer disease together with vascular dementia.
Potempa LA, Rajab IM, Olson ME, Hart PC. C-Reactive Protein and Cancer: Interpreting the Differential Bioactivities of Its Pentameric and Monomeric, Modified Isoforms. Front Immunol. 2021 Sep 6;12:744129. doi: 10.3389/fimmu.2021.744129. PMID: 34552600; PMCID: PMC8450391.
Slevin M, García-Lara E, Capitanescu B, Sanfeliu C, Zeinolabediny Y, AlBaradie R, Olah P, Guo B, Pirici D, Di Napoli M, Popa-Wagner A. Monomeric C-Reactive Protein Aggravates Secondary Degeneration after Intracerebral Haemorrhagic Stroke and May Function as a Sensor for Systemic Inflammation. J Clin Med. 2020 Sep 22;9(9):3053. doi: 10.3390/jcm9093053. PMID: 32971821; PMCID: PMC7563733.
Al-Baradie RS, Pu S, Liu D, Zeinolabediny Y, Ferris G, Sanfeli C, Corpas R, Garcia-Lara E, Alsagaby SA, Alshehri BM, Abdel-Hadi AM, Ahmad F, Moatari P, Heidari N, Slevin M. Monomeric C-Reactive Protein Localized in the Cerebral Tissue of Damaged Vascular Brain Regions Is Associated With Neuro-Inflammation and Neurodegeneration-An Immunohistochemical Study. Front Immunol. 2021 Mar 16;12:644213. doi: 10.3389/fimmu.2021.644213. PMID: 33796111; PMCID: PMC8007856.
- García-Lara E, Aguirre S, Clotet N, Sawkulycz X, Bartra C, Almenara-Fuentes L, Suñol C, Corpas R, Olah P, Tripon F, Crauciuc A, Slevin M, Sanfeliu C. Antibody Protection against Long-Term Memory Loss Induced by Monomeric C-Reactive Protein in a Mouse Model of Dementia. Biomedicines. 2021 Jul 16;9(7):828. doi: 10.3390/biomedicines9070828. PMID: 34356892; PMCID: PMC8301488.
Gan Q, Wong A, Zhang Z, Na H, Tian H, Tao Q, Rajab IM, Potempa LA, Qiu WQ. Monomeric C-reactive protein induces the cellular pathology of Alzheimer's disease. Alzheimers Dement (N Y). 2022 Jul 8;8(1):e12319. doi: 10.1002/trc2.12319. PMID: 35846159; PMCID: PMC9270638.
Ilex Life Sciences is an authorized distributor of PromedeusLab mCRP Human ELISA.