Increased YKL-40 But Not C-Reactive Protein Levels in Patients With Alzheimer’s DiseaseⅠ
Apr 11, 2023
Abstract: Neuroinflammation is a common feature in Alzheimer’s (AD) and Parkinson’s (PD) diseases. In the last few decades, a testable hypothesis was proposed that protein-unfolding events might occur due to neuroinflammatory cascades involving alterations in the crosstalk between glial cells and neurons. Here, we tried to clarify the pattern of two of the most promising biomarkers of neuroinflammation in cerebrospinal fluid (CSF) in AD and PD. This study included cognitively unimpaired elderly patients, patients with mild cognitive impairment, patients with AD dementia, and patients with PD.
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CSF samples were analyzed for YKL-40 and C-reactive protein (CRP). We found that CSF YKL-40 levels were significantly increased only in the dementia stages of AD. Additionally, increased YKL-40 levels were found in the cerebral orbitofrontal cortex from AD patients in agreement with augmented astrogliosis. Our study confirms that these biomarkers of neuroinflammation are differently detected in CSF from AD and PD patients.
Keywords: Alzheimer’s disease; Parkinson’s disease; YKL-40; C-reactive protein; CSF and plasma biomarkers; inflammation; astrogliosis
1 Introduction
Neuroinflammation is now widely accepted as a pathological hallmark of Alzheimer’s (AD) [1,2] and Parkinson’s (PD) [3–5] disease. Several damage signals appear to induce neuroinflammation, including β-amyloid (Aβ) oligomers, tau, and α-synuclein (α-syn), mediated by the progressive astrocyte and microglial cell activation with the consequent overproduction of proinflammatory agents that may leak toward cerebrospinal fluid (CSF) [6].
Despite the analysis of these agents in CSF being a tempting topic to study, levels of inflammatory markers in CSF from AD and PD patients have not been sufficiently investigated. A standard clinical application of inflammatory markers in the clinical diagnosis of these neurodegenerative disorders is lacking, likely owing to contradictory and heterogeneous findings of numerous studies [7,8]. Among these neuroinflammatory markers found in biological samples is YKL-40 (also named Chitinase 3-like I).
This marker has been largely associated with the pathogenesis of a variety of human diseases, many of them sharing chronic inflammatory features and high cellular activity, including rheumatoid arthritis, hepatic fibrosis, and asthma, where YKL-40 levels were found elevated in patient peripheral blood [9–11]. YKL-40 is a secreted glycoprotein with functions including tissue remodeling during inflammation and angiogenic processes, which make YKL-40 a good marker of inflammation and endothelial dysfunction [12–14].
YKL-40 was found elevated in CSF from several acute and chronic neuroinflammatory conditions [15], as well as in preclinical and prodromal AD/mild cognitive impairment (MCI) [16–18]. This is consistent with the potential role of astrocytosis in early AD pathogenesis [19] and with the fact that YKL-40 expression and YKL-40 protein levels are abundant in reactive astrocytes and residual in microglial cells [15,20,21].
Additionally, YKL-40 was found close to amyloid plaques and neurofibrillary tangles in AD [16]. Contrarily, other works reported different results showing no significant differences in YKL-40 levels in CSF from MCI and AD patients compared with cognitively normal subjects [22]. Other works indicated increased CSF YKL-40 levels only in AD but not in MCI subjects compared with healthy controls [23,24].
Regarding PD, YKL-40 concentrations in CSF were found either decreased or unchanged [25,26]. Although YKL-40 can be considered one of the most promising neuroinflammatory biomarkers in AD, the abovementioned works indicate that brain YKL-40 levels patterns in different neurodegenerative diseases and the potential correlation between brain and CSF levels are largely unknown, indicating that more research regarding YKL-40 expression pattern is required.
On the other hand, C-reactive protein (CRP), a kind of acute-phase protein regulated by proinflammatory cytokines, is the most studied biomarker of systemic inflammation [27]. CRP was linked to chronic inflammatory and neurodegenerative diseases, such as AD and PD [28]. Elevated CRP peripheral blood levels have been frequently associated with an increased risk of dementia and cognitive decline.
Studies carried out investigating the association between markers of inflammation and the risk of dementia showed conflicting results. A systematic review and meta-analysis found that the elevation of peripheral CRP levels was associated with an increased risk of developing dementia [29]. Nevertheless, another meta-analysis found no significant differences in serum CRP levels between patients with AD and healthy subjects [30].
Epidemiological studies have also explored the relationship between CRP levels and AD risk, describing lower CRP levels in CSF from AD patients [31,32]. Regarding PD and CRP levels, results in the literature are still contradictory. A significant increase in blood CRP levels was reported in subjects suffering from PD compared with healthy controls [33,34], while other works did not identify such a tendency, instead reporting no differences [35].
Furthermore, the CRP levels in CSF remained unchanged in PD patients when compared with healthy subjects [26,32]. Despite these differences, CRP is considered a prominent “risk factor” for PD [36]. Growing evidence indicates that blood-borne CRP can cross the blood–brain, and blood–spinal cord barriers; thus, CRP can be found in the CSF and deposited in the diseased central nervous system (CNS). The source of CRP might also be local.
However, CRP production may occur in multiple CNS-resident cells including neurons, microglia, and astrocytes [37–39]. Regardless of its origin (hepatic versus local), the presence of CRP in the CNS is associated with numerous diseases including AD [40]. CRP levels were also found to increase in brain parenchyma tissue after intracerebral hemorrhage [41].
Additionally, large amounts of the protein were present in perihematomal regions and within neurons and glia of patients who died within 12 h of spontaneous intracerebral hemorrhage [41,42]. Despite these accumulative data supporting a role of neuroinflammation, particularly YKL-40 and CRP in AD and PD, there is no definitive evidence reflecting the peripheral (blood) and central (CSF) concentration changes of YKL-40 and CRP in AD and/or PD patients.
We think that further research is needed to elucidate the variable pattern of these inflammatory biomarkers in the CSF and blood from AD and PD patients. In this work, we aimed to clarify YKL-40 and CRP concentrations measured in CSF and plasma and to determine their specificity in AD and PD. To address this issue, we analyzed YKL-40 and CRP levels in CSF and plasma from a well-characterized cohort of patients with MCI, AD, and PD, using sensitive enzyme-linked immunosorbent assays (ELISAs).
The mechanism of Cistanche treatment AD&PD
Cistanche is an herb that has been traditionally used in Chinese medicine to treat a variety of health conditions, including neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD).
Cistanche contains several bioactive compounds, including phenylethanoid glycosides and iridoid glycosides, which have antioxidant, anti-inflammatory, and neuroprotective effects. These compounds help to protect neuronal cells from damage caused by free radicals and inflammatory processes, which are believed to contribute to the development and progression of AD and PD.
Additionally, Cistanche has been shown to increase the levels of certain neurotransmitters in the brain, including dopamine and acetylcholine, which are important for normal brain function. By increasing these neurotransmitter levels, Cistanche may help to improve cognitive function and reduce the symptoms of AD and PD.
Overall, the mechanisms of Cistanche in treating AD and PD involve its antioxidant, anti-inflammatory, and neuroprotective effects, as well as its ability to enhance neurotransmitter levels in the brain.
to be continued...
Víctor Antonio Blanco-Palmero 1,2,3,† , Marcos Rubio-Fernández 1,2,†, Desireé Antequera 1,2 , Alberto Villarejo-Galende 1,2,3 , José Antonio Molina 1,2,3, Isidro Ferrer 1,4,5,6 , Fernando Bartolome 1,2,* and Eva Carro 1,2,*
1 Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; victorb1989@gmail.com (V.A.B.-P.); marcosrubio.imas12@h12o.es (M.R.-F.); eeara@yahoo.es (D.A.); avgalende@yahoo.es (A.V.-G.); cvillaiza@telefonica.net (J.A.M.); 8082ifa@gmail.com (I.F.)
2 Group of Neurodegenerative Diseases, Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain
3 Neurology Service Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
4 Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, E08907 Barcelona, Spain
5 Department of Pathology and Experimental Therapeutics, University of Barcelona, E08900 Barcelona, Spain 6 Institute of Neurosciences, University of Barcelona, E08000 Barcelona, Spain * Correspondence: fbartolome.imas12@h12o.es (F.B.); carroeva@h12o.es (E.C.); Tel.: +34-913908765 (F.B. & E.C.); Fax: +34-913908544 (F.B. & E.C.)
