Monomeric C-Reactive Protein Localized in the Cerebral Tissue of Damaged Vascular Brain Regions Is Associated With Neuro-Inflammation and Neurodegeneration-An Immunohistochemical Study.

Raid S Al-Baradie,Bader M Alshehri,Psalm Moatari,Yasmin Zeinolabediny,Glenn Ferris,Shuang Pu,Shuang Pu,Ahmed M Abdel-Hadi,Nima Heidari,Ruben Corpas,Coral Sanfeli,Elisa Garcia-Lara,Mark Slevin,Mark Slevin,Donghui Liu,Fuzail Ahmad,Suliman A Alsagaby

doi:10.3389/fimmu.2021.644213

Abstract

Monomeric C-reactive protein (mCRP) is now accepted as having a key role in modulating inflammation and in particular, has been strongly associated with atherosclerotic arterial plaque progression and instability and neuroinflammation after stroke where a build-up of the mCRP protein within the brain parenchyma appears to be connected to vascular damage, neurodegenerative pathophysiology and possibly Alzheimer's Disease (AD) and dementia. Here, using immunohistochemical analysis, we wanted to confirm mCRP localization and overall distribution within a cohort of AD patients showing evidence of previous infarction and then focus on its co-localization with inflammatory active regions in order to provide further evidence of its functional and direct impact. We showed that mCRP was particularly seen in large amounts within brain vessels of all sizes and that the immediate micro-environment surrounding these had become laden with mCRP positive cells and extra cellular matrix. This suggested possible leakage and transport into the local tissue. The mCRP-positive regions were almost always associated with neurodegenerative, damaged tissue as hallmarked by co-positivity with pTau and β-amyloid staining. Where this occurred, cells with the morphology of neurons, macrophages and glia, as well as smaller microvessels became mCRP-positive in regions staining for the inflammatory markers CD68 (macrophage), interleukin-1 beta (IL-1β) and nuclear factor kappa B (NFκB), showing evidence of a perpetuation of inflammation. Positive staining for mCRP was seen even in distant hypothalamic regions. In conclusion, brain injury or inflammatory neurodegenerative processes are strongly associated with mCRP localization within the tissue and given our knowledge of its biological properties, it is likely that this protein plays a direct role in promoting tissue damage and supporting progression of AD after injury.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, a brain degenerative disease affecting 1:14 of the population over 65 years of age [1]
This is an important observation as here and previously, we showed what appears to be a transmission of monomeric C-reactive protein (mCRP) via the vasculature from the hippocampus to distant regions of the hypothalamus in addition to other regions of the cortex suggesting it can be carried from the original site of vascular penetration, possibly aiding or even instigating neuroinflammation across the brain
We have shown local release of mCRP into brain parenchymal tissue and a concomitant activation of regional and focal blood vessels, and strong co-staining with markers of inflammation and inflammatory infiltrating cells

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, a brain degenerative disease affecting 1:14 of the population over 65 years of age [1]. Our previous work showed that monomeric C-reactive protein (mCRP) is found in large amounts in the parenchyma following ischemic or hemorrhagic stroke and appears to originate mainly from blood vessel leakage into the local surrounding tissue [3, 4]. Dementia of vascular origin is associated with damage to the deep penetrating arteries within the parenchyma and this can result from head trauma, ischemic, or hemorrhagic stroke or linked to genetic abnormalities in younger patients [5, 6]. C-reactive protein in general, has been used in the fields of cardiovascular disease and autoimmune conditions as well as sepsis to indicate levels of inflammation, over the last decade, its monomeric form (mCRP) has been highlighted as the major biologically active form, and both circulating levels of CRP as well as tissue-associated mCRP within the brain have been shown to be associated with development of dementia [10]

Results

Discussion

Conclusion