Influence of Alpha-2-Macroglobulin 5 bp I/D and Ile1000Val Polymorphisms on the Susceptibility of Alzheimer’s disease: A Systematic Review and Meta-analysis of 52 Studies

Chen, Hui; Li, Zhongxuan; Liu, Nan; Zhang, Weiwei; Zhu, Guangming

doi:10.1007/s12013-014-9950-3

Cited by 8 publications

(11 citation statements)

References 65 publications

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“…It has been demonstrated that α2M −/− mice are resistant to the lethal effects of lipopolysaccharides 16 . α2M is also implicated in Alzheimer disease (AD) due to its ability to mediate the clearance and degradation of α-beta, the major component of beta-amyloid deposits 17 . However, role of α2M is yet to be determined in WNV infection and other inflammatory infectious diseases.…”

Section: Resultsmentioning

confidence: 99%

Identification of host genes leading to West Nile virus encephalitis in mice brain using RNA-seq analysis

Kumar

Belcaid

Nerurkar

2016

Sci Rep

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Differential host responses may be critical determinants of distinct pathologies of West Nile virus (WNV) NY99 (pathogenic) and WNV Eg101 (non-pathogenic) strains. We employed RNA-seq technology to analyze global differential gene expression in WNV-infected mice brain and to identify the host cellular factors leading to lethal encephalitis. We identified 1,400 and 278 transcripts, which were differentially expressed after WNV NY99 and WNV Eg101 infections, respectively, and 147 genes were common to infection with both the viruses. Genes that were up-regulated in infection with both the viruses were mainly associated with interferon signaling. Genes associated with inflammation and cell death/apoptosis were only expressed after WNV NY99 infection. We demonstrate that differences in the activation of key pattern recognition receptors resulted in the induction of unique innate immune profiles, which corresponded with the induction of interferon and inflammatory responses. Pathway analysis of differentially expressed genes indicated that after WNV NY99 infection, TREM-1 mediated activation of toll-like receptors leads to the high inflammatory response. In conclusion, we have identified both common and specific responses to WNV NY99 and WNV Eg101 infections as well as genes linked to potential resistance to infection that may be targets for therapeutics.

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Section: Resultsmentioning

confidence: 99%

Identification of host genes leading to West Nile virus encephalitis in mice brain using RNA-seq analysis

Kumar

Belcaid

Nerurkar

2016

Sci Rep

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“…18–21 Moreover, early candidate gene analyses suggested that polymorphic variation in the A2M gene are associated with increased risk of AD, although these were not replicated in larger studies. 22,23 …”

Section: Introductionmentioning

confidence: 99%

Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway

Varma²,

et al. 2016

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Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer’s disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer’s Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.

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“…[21,22] Due to its protease inhibitory function, it can enhance procoagulant properties and possesses radioprotective effects. [23] In the eye, α 2 M is produced by retinal glia [11,12] and was found elevated as a soluble factor in the aqueous humor of eyes with glaucoma. [13] As true for other key proteins, α 2 M function is multifactorial, and includes, inhibiting the neuroprotective activity of nerve growth factor (NGF) through TrkA receptors, and enhanced the neurotoxic effect of proNGF through p75NTR receptor, α 2 M-LRP1 interactions, and immune bystander effects as well as glutamatergic stress.…”

Section: Discussionmentioning

confidence: 99%

Variable expression of alpha-2-macroglobulin and tumor necrosis factor-α in the aqueous humor of patients with pseudoexfoliative syndrome with and without glaucoma

Barcelona¹,

Schaap-Fogler²,

Garcia³

et al. 2018

cleverjournal

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Purpose: The purpose of this study was to explore the involvement of two known mediators of the apoptotic processes in ganglion cells, the proteins alpha-2-macroglobulin (α2M) and tumor necrosis factor-α (TNF-α), in the pathogenesis of primary open-angle glaucoma (POAG) and pseudoexfoliation (PXF) syndrome. Methods: Aqueous humor samples were collected at the beginning of cataract surgery. Levels of α 2 M and TNF-α were measured using western blot analysis and expressed as fold values. Commercially available pure α 2 M protein and TNF-α were used as controls. For digital quantification, nitrocellulose membranes were scanned and analyzed using Image J software. Results: Levels of α2M level were measured in 61 samples, which included 18 with PXF, 15 with POAG, and 28 controls. Mean levels of α 2 M in the aqueous humor of patients with PXF without glaucoma were comparable to control levels and lower than for patients with POAG (0.63 ± 0.1; 0.6 ± 0.05; and 0.92 ± 0.1, respectively, P = 0.05). TNF-α levels were measured in 25 aqueous humor samples including eight with PXF, seven with POAG, and 10 controls. TNF-α protein fold level values were higher in patients with glaucoma, with and without PXF, and compared to control values (0.77 ± 0.1 and 0.5 ± 0.4 compared to 0.06 ± 0.01, respectively, P = 0.05 post-log conversion). Conclusion: This work further documents the role of α2M protein in the apoptotic process in ganglion cells related to increased IOP but marks its absence in PXF material accumulation without glaucoma. Our findings regarding TNF-α levels may still suggest a role for this protein in PXF syndrome alone.

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Influence of Alpha-2-Macroglobulin 5 bp I/D and Ile1000Val Polymorphisms on the Susceptibility of Alzheimer’s disease: A Systematic Review and Meta-analysis of 52 Studies

Cited by 8 publications

References 65 publications

Identification of host genes leading to West Nile virus encephalitis in mice brain using RNA-seq analysis

Identification of host genes leading to West Nile virus encephalitis in mice brain using RNA-seq analysis

Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway

Variable expression of alpha-2-macroglobulin and tumor necrosis factor-α in the aqueous humor of patients with pseudoexfoliative syndrome with and without glaucoma

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