Complement factor H levels are decreased and correlated with serum C-reactive protein in late-onset Alzheimer's disease

Lu, Guo; Liu, Weihong; Huang, Xin; Zhao, Yanxin

doi:10.1590/0004-282x20190151

Cited by 10 publications

(9 citation statements)

References 25 publications

(25 reference statements)

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“…Elevated levels of ROS and oxidative stress have been linked to increased levels of C‐reactive protein (CRP) in various diseases (Cervantes‐Gracia et al., 2020; Cottone et al., 2006; Kauppinen et al., 2016; Oberg et al., 2004). FH, which is involved in regulating the CS, has been found to have a positive correlation with CRP levels (Chirco & Potempa, 2018; Lu et al., 2020). Additionally, CRP has been shown to inactivate the AP of the CS (Jarva et al., 1999; Mold et al., 1984).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial damage and clearance in retinal pigment epithelial cells

Gurubaran

2024

Acta Ophthalmologica

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Age‐related macular degeneration (AMD) is a devastating eye disease that causes permanent vision loss in the central part of the retina, known as the macula. Patients with such severe visual loss face a reduced quality of life and are at a 1.5 times greater risk of death compared to the general population. Currently, there is no cure for or effective treatment for dry AMD. There are several mechanisms thought to underlie the disease, for example, ageing‐associated chronic oxidative stress, mitochondrial damage, harmful protein aggregation and inflammation. As a way of gaining a better understanding of the molecular mechanisms behind AMD and thus developing new therapies, we have created a peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha and nuclear factor erythroid 2‐related factor 2 (PGC1α/NFE2L2) double‐knockout (dKO) mouse model that mimics many of the clinical features of dry AMD, including elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen‐like structures in retinal pigment epithelial cells (RPE). In addition, a human RPE cell‐based model was established to examine the impact of non‐functional intracellular clearance systems on inflammasome activation. In this study, we found that there was a disturbance in the autolysosomal machinery responsible for clearing mitochondria in the RPE cells of one‐year‐old PGC1α/NFE2L2‐deficient mice. The confocal immunohistochemical analysis revealed an increase in autophagosome marker microtubule‐associated proteins 1A/1B light chain 3B (LC3B) as well as multiple mitophagy markers such as PTE‐induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN), along with signs of damaged mitochondria. However, no increase in autolysosome formation was detected, nor was there a colocalization of the lysosomal marker LAMP2 or the mitochondrial marker, ATP synthase β. There was an upregulation of late autolysosomal fusion Ras‐related protein (Rab7) in the perinuclear space of RPE cells, together with autofluorescent aggregates. Additionally, we observed an increase in the numbers of Toll‐like receptors 3 and 9, while those of NOD‐like receptor 3 were decreased in PGC1α/NFE2L2 dKO retinal specimens compared to wild‐type animals. There was a trend towards increased complement component C5a and increased involvement of the serine protease enzyme, thrombin, in enhancing the terminal pathway producing C5a, independent of C3. The levels of primary acute phase C‐reactive protein and receptor for advanced glycation end products were also increased in the PGC1α/NFE2L2 dKO retina. Furthermore, selective proteasome inhibition with epoxomicin promoted both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial‐mediated oxidative stress, leading to the release of mitochondrial DNA to the cytosol, resulting in potassium efflux‐dependent activation of the absent in melanoma 2 (AIM2) inflammasome and the subsequent secretion of interleukin‐1β in ARPE‐19 cells. In conclusion, the data suggest that there is at least a relative decrease in mitophagy, increases in the amounts of C5 and thrombin and decreased C3 levels in this dry AMD‐like model. Moreover, selective proteasome inhibition evoked mitochondrial damage and AIM2 inflammasome activation in ARPE‐19 cells.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial damage and clearance in retinal pigment epithelial cells

Gurubaran

2024

Acta Ophthalmologica

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“…Accordingly, alterations of their levels could be related to NPS in the context of AD. CFAH was found to be decreased in patients with late‐onset AD dementia (Lu et al, 2020), but not consistently (Williams et al, 2015). Elevated levels of CRP predicted poorer cognition and increased the dementia risk in cognitively healthy adults under the age of 80.…”

Section: Discussionmentioning

confidence: 99%

Blood plasma protein profiles of neuropsychiatric symptoms and related cognitive decline in older people

Rabl

Clark

Dayon

et al. 2022

Journal of Neurochemistry

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Neuropsychiatric symptoms (NPS) severely affect patients and their caregivers, and are associated with worse long‐term outcomes. This study tested the hypothesis that altered protein levels in blood plasma could serve as biomarkers of NPS; and that altered protein levels are associated with persisting NPS and cognitive decline over time. We performed a cross‐sectional and longitudinal study in older subjects with cognitive impairment and cognitively unimpaired in a memory clinic setting. NPS were recorded through the Neuropsychiatric Inventory Questionnaire (NPI‐Q) while cognitive and functional impairment was assessed using the clinical dementia rating sum of boxes (CDR‐SoB) score at baseline and follow‐up visits. Shotgun proteomic analysis based on liquid chromatography‐mass spectrometry was conducted in blood plasma samples, identifying 420 proteins. The presence of Alzheimer's Disease (AD) pathology was determined by cerebrospinal fluid biomarkers. Eighty‐five subjects with a mean age of 70 (±7.4) years, 62% female and 54% with mild cognitive impairment or mild dementia were included. We found 15 plasma proteins with altered baseline levels in participants with NPS (NPI‐Q score > 0). Adding those 15 proteins to a reference model based on clinical data (age, CDR‐SoB) significantly improved the prediction of NPS (from receiver operating characteristic area under the curve [AUC] 0.75 to AUC 0.91, p = 0.004) with a specificity of 89% and a sensitivity of 74%. The identified proteins additionally predicted both persisting NPS and cognitive decline at follow‐up visits. The observed associations were independent of the presence of AD pathology. Using proteomics, we identified a panel of specific blood proteins associated with current and future NPS, and related cognitive decline in older people. These findings show the potential of untargeted proteomics to identify blood‐based biomarkers of pathological alterations relevant for NPS and related clinical disease progression.

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“…Oxidative stress and elevated ROS levels have been claimed to increase the CRP level in various diseases [19,[28][29][30][31][32]. FH is involved in regulating the CS and known to correlate positively with CRP levels [33,34]. Moreover, CRP is able to inactivate the AP of the CS [35,36].…”

Section: Crp and Rage Coordinate Under Oxidative Stressmentioning

confidence: 99%

Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

Gurubaran

Heloterä

Marry

et al. 2021

Biology

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Aging-associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g., age-related macular degeneration (AMD). Previously, we reported the presence of dry AMD-like signs, such as elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the retinal pigment epithelial (RPE) cells of nuclear factor erythroid 2-related factor 2, and a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (NFE2L2/PGC1α) double knockout (dKO) mouse model. Here, we investigated the dynamics of inflammatory markers in one-year-old NFE2L2/PGC1α dKO mice. Immunohistochemical analysis revealed an increase in levels of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in NFE2L2/PGC1α dKO retinal specimens as compared to wild type animals. Further analysis showed a trend towards an increase in complement component C5a independent of component C3, observed to be tightly regulated by complement factor H. Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detected an increase in primary acute phase C-reactive protein and receptor for advanced glycation end products in NFE2L2/PGC1α dKO retina. Our main data show C5 and thrombin upregulation together with decreased C3 levels in this dry AMD-like model. In general, the retina strives to mount an orchestrated inflammatory response while attempting to maintain tissue homeostasis and resolve inflammation.

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Complement factor H levels are decreased and correlated with serum C-reactive protein in late-onset Alzheimer's disease

Cited by 10 publications

References 25 publications

Mitochondrial damage and clearance in retinal pigment epithelial cells

Mitochondrial damage and clearance in retinal pigment epithelial cells

Blood plasma protein profiles of neuropsychiatric symptoms and related cognitive decline in older people

Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

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