Glia Maturation Factor Expression in Entorhinal Cortex of Alzheimer’s Disease Brain

Thangavel, Ramasamy; Kempuraj, Duraisamy; Stolmeier, Deirdre; Anantharam, Poojya; Khan, Mohammad Moshahid; Zaheer, Asgar

doi:10.1007/s11064-013-1080-6

Cited by 31 publications

(35 citation statements)

References 43 publications

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“…Earlier studies from our laboratory has shown the co-localization of GMF with Aβ and p-tau in human AD brains [41]. Human AD post-mortem brain and age-matched non-AD control brain tissue from different cases were analyzed by immunofluorescence staining to determine the expression and co-localization of amyloid-β and hyper-phosphorylated tau with GMF using the respective antibodies.…”

Section: Resultsmentioning

confidence: 99%

Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain

Ahmed

Iyer

Thangavel

et al. 2017

JAD

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyper-phosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid–β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 inflammasome and autophagy-lysosomal markers in relation to Aβ, p-tau and GMF in human post-mortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human post-mortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the amyloid plaques and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, amyloid beta and hyper-phosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the autophagosomal pathway.

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Section: Resultsmentioning

confidence: 99%

Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain

Ahmed

Iyer

Thangavel

et al. 2017

JAD

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“…GMF is expressed in astrocytes, microglia and many neurons in the brains and the expression is increased in neurodegenerative diseases (Wang et al, 1992; Zaheer et al, 2011a; Thangavel et al, 2013). We have previously reported that GMF-induces neurodegeneration by acting on glial cells and neurons (Lim et al, 2004; Zaheer et al, 2008a; Zaheer et al, 2008b; Kempuraj et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Kempuraj

Selvakumar

Zaheer

et al. 2017

J Neuroimmune Pharmacol

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Parkinson’s disease (PD) is a progressive movement disorder characterized by neuroinflammation and dopaminergic neurodegeneration in the brain. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces the release of inflammatory mediators from glial cells and neurons. Glia maturation factor (GMF), a brain proinflammatory protein, MPP+, and mast cell-derived inflammatory mediators induce neurodegeneration which eventually leads to PD. However, the precise mechanisms underlying interaction between glial cells, neurons and mast cells in PD still remain elusive. In the present study, mouse bone marrow-derived mast cells (BMMCs) and mouse fetal brain-derived mixed glia/neurons, astrocytes and neurons were incubated with MPP+, GMF and mast cell-derived inflammatory mediators mouse mast cell protease-6 (MMCP-6), MMCP-7 or tryptase/brain-specific serine protease-4 (tryptase/BSSP-4). Inflammatory mediators released from these cells in the culture medium were quantitated by enzyme-linked immunosorbent assay. Neurodegeneration was quantified by measuring total neurite outgrowth following microtubule-associated protein-2 immunocytochemistry. MPP+− induced significant neurodegeneration with reduced total neurite outgrowth. MPP+− induced the release of tryptase/BSSP-4 from the mouse mast cells, and tryptase/BSSP-4 induced chemokine (C-C motif) ligand 2 (CCL2) release from astrocytes and glia/neurons. Overall our results suggest that MPP+, GMF, MMCP-6 or MMCP-7 stimulate glia/neurons, astrocytes or neurons to release CCL2 and matrix metalloproteinase-3. Additionally, CD40L expression is increased in BMMCs after incubation with MPP+ in a co-culture system consisting of BMMCs and glia/neurons. We propose that mast cell interaction with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD.

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“…Briefly, the sections were heated in citrate buffer (10 mM citric acid in dH 2 O) for 1 min for antigen retrieval and then incubated for 30 min in 0.3% H 2 O 2 in PBS as we have reported previously [20]. Then the sections were blocked for 1 h with 5% normal goat serum containing 3% bovine serum albumin (BSA) with 0.3% Triton-X 100, diluted in PBS.…”

Section: Methodsmentioning

confidence: 99%

“…To quantitate the IL-33 and ST2 immunostaining, we have counted IL-33-positive and ST2-positive cells in the entorhinal cortex of AD (and non-AD brains as we have reported previously [20]. The counting was performed under 400× in five different fields and then averaged.…”

Section: Methodsmentioning

confidence: 99%

Alzheimer's Disease: Evidence for the Expression of Interleukin-33 and Its Receptor ST2 in the Brain

Xiong

Thangavel

Kempuraj

et al. 2014

JAD

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Inflammatory responses are increasingly implicated in the pathogenesis of neurodegenerative diseases such as in Alzheimer’s disease (AD). Interleukin-33 (IL-33), a member of IL-1 family, is constitutively expressed in the central nervous system and thought to be an important mediator of glial cell response to neuropathological lesions. Proinflammatory molecules are highly expressed at the vicinity of amyloid plaques (APs) and neurofibrillary tangles (NFTs), the hallmarks of AD pathology. We have investigated the expression of IL-33 and ST2 in relation to APs and NFTs in human AD and non-AD control brains by immunohistochemistry. Sections from the entorhinal cortex, where APs and NFTs appear in early stages of AD, were used for immunohistochemistry. Mouse primary astrocytes were cultured and incubated with amyloid-β1–42 (Aβ1–42), component of plaque for 72 h and analyzed for the expression of IL-33 by flow cytometry. We found strong expression of IL-33 and ST2 in the vicinity of Aβ and AT8 labelled APs and NFTs respectively, and in the glial cells in AD brains when compared to non-AD control brains. IL-33 and ST2 positive cells were also significantly increased in AD brains when compared to non-AD brains. Flow cytometric analysis revealed incubation of mouse astrocytes with Aβ1–42 increased astrocytic IL-33 expression in vitro. These results suggest that IL-33, an alamin cytokine, may induce inflammatory molecule release from the glial cells and may play important role in the pathogenesis of AD.

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Glia Maturation Factor Expression in Entorhinal Cortex of Alzheimer’s Disease Brain

Cited by 31 publications

References 43 publications

Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain

Co-Localization of Glia Maturation Factor with NLRP3 Inflammasome and Autophagosome Markers in Human Alzheimer’s Disease Brain

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

Alzheimer's Disease: Evidence for the Expression of Interleukin-33 and Its Receptor ST2 in the Brain

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