Microglia, Alzheimer's Disease, and Complement

Crehan, Helen; Hardy, John; Pocock, Jennifer M.

doi:10.1155/2012/983640

Cited by 62 publications

(62 citation statements)

References 126 publications

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“…When activated, microglia proliferate, form nodules to surround areas of damage, and secrete cytokines/chemokines to recruit immune cells (47)(48)(49)(50)(51)(52)(53). Despite different triggering events, microglia activation is a major characteristic of neurodegenerative conditions, including Alzheimer's disease, Parkinson's diseases, traumatic brain injury, and multiple sclerosis (54)(55)(56)(57). Similarly, when activated, astrocytes proliferate and are potent producers of cytokines/chemokines (51).…”

Section: Discussionmentioning

confidence: 99%

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Bardina

Brown

Michlmayr

et al. 2017

J Virol

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West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. IMPORTANCEIn this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.KEYWORDS arbovirus, cell trafficking, chemokine receptors, chemokines, hostpathogen interactions, leukocytes, neuroimmunology, viral pathogenesis W est Nile virus (WNV) is a mosquito-transmitted flavivirus that was introduced into the United States in 1999 (1). Since then, the virus has spread rapidly across the continent and has become the leading cause of arthropod-borne virus-induced encephalitis in the United States. WNV is a significant public health concern due to the unpredictable nature of annual disease outbreaks and the lack of specific therapeutics and vaccines for human use (2). In humans, WNV is transmitted through the bite of an infected mosquito. The outcome of infection ranges from asymptomatic to severe neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis (3)(4)(5)

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Section: Discussionmentioning

confidence: 99%

Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Bardina

Brown

Michlmayr

et al. 2017

J Virol

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“…[1] Microglial cells perform a variety of different functions within the CNS related to the immune response and the maintenance of cellular homeostasis. Much interest has focused on the role of microglia in neurodegenerative diseases (particularly Alzheimer's disease (AD)) in recent times due to an increasing number of genetic and biomarker discovery programs and growing evidence to suggest that inflammation has a role in disease pathogenesis.…”

mentioning

confidence: 99%

Combined tissue and fluid proteomics with Tandem Mass Tags to identify low-abundance protein biomarkers of disease in peripheral body fluid: An Alzheimer's Disease case study

Russell

Heslegrave

Mitra

et al. 2016

Rapid Commun. Mass Spectrom.

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RATIONALE:Ideal biomarkers are present in readily accessible samples including plasma and cerebrospinal fluid (CSF), and are directly derived from diseased tissue, therefore likely to be of relatively low abundance. Traditional unbiased proteomic approaches for biomarker discovery have struggled to detect low-abundance markers due to the high dynamic range of proteins, the predominance of hyper-abundant proteins, and the use of data-dependent acquisition mass spectrometry (MS). To overcome these limitations and improve biomarker discovery in peripheral fluids, we have developed TMTcalibrator ™ ; a novel MS workflow combining isobarically labelled diseased tissue digests in parallel with an appropriate set of labelled body fluids to increase the chance of identifying low-abundance, tissue-derived biomarkers. METHODS: A disease relevant cell line was labelled with TMT® in a range of concentrations generating a multi-point calibration curve. Peripheral biofluid samples were labelled with the remaining tags and quantitative analysis was performed using an Orbitrap Fusion Tribrid mass spectrometer with a Top10 CID-HCD MS3 synchronous precursor selection (SPS) method. SPS allowed direct analysis of non-depleted, unfractionated CSF samples with complete profiling of six individual samples requiring only 15 hours of MS time, equivalent to 1.5 h per sample. RESULTS: Using the TMTcalibrator ™ workflow allowed the identification of several markers of microglia activation that are differentially quantified in the CSF of patients with Alzheimer's disease (AD). We report peptides from 41 proteins that have not previously been detected in the CSF, that appear to be regulated by at least 60% in AD.CONCLUSIONS: This study has demonstrated the benefits of the new TMTcalibrator ™ workflow and the results suggest this is a suitable and efficient method of detecting low-abundance peptides within biological fluids. The use of TMTcalibrator ™ in further biomarker discovery studies should be considered to overcome some of the limitations commonly associated with more conventional approaches.

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“…Some research articles indicated that the microglial activity could be manipulated by the complement factors towards protective or harmful [18]. Various research groups tried to show the role of complement system in Alzheimer's disease and also trying to find out the suitable therapeutic approaches targeting complement system as mentioned in Table 2.…”

Section: Immunotherapeutic Approachmentioning

confidence: 99%

“…The purpose of this review article is to brief cellular neuroimmunological aspects of AD, describes advances in the use of immunotherapy for treatment of AD and highlights ongoing efforts to develop novel therapies. complement system in AD [18]. There are many possible approaches which can Neurons can generate the inflammatory molecules and can serve as source of complement systems and others.…”

Section: Introductionmentioning

confidence: 99%