GM1 induces p38 and microtubule dependent ramification of rat primary microglia in vitro

Park, Jiyoung; Kim, Hee Young; Jou, Ilo; Park, Sang Myun

doi:10.1016/j.brainres.2008.09.072

Cited by 18 publications

(12 citation statements)

References 58 publications

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“…Likewise, we were not able to trigger YB-1 expression (mRNA/protein) in BV-2 cells through the addition of LPS despite the well-established capacity of LPS to activate BV-2 cells (Henn et al, 2009). Both results agree with previous findings that LPS, while able to induce hypotrophy in cultured primary microglia, is not able to induce the transformation of microglia into the amoeboid form with a loosened ramified appearance (Kloss et al, 2001, Park et al, 2008. The authors mentioned that in the adult brain, the transformation of microglia into the amoeboid form normally only occurres in association with neural cell debris such as what is observed in severe forms of brain pathology.…”

Section: Discussionsupporting

confidence: 91%

Constitutive and functional expression of YB-1 in microglial cells

et al. 2015

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Section: Discussionsupporting

confidence: 91%

Constitutive and functional expression of YB-1 in microglial cells

et al. 2015

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“…Activation of p38 MAPK is required for cytoskeleton re-arrangement and subsequent autophagy (Park et al, 2008; Tang et al, 2008). The small GTPase Rac has been implicated in membrane ruffling and phagocytosis (Ridley et al, 1992; Cox et al, 1997), and its activation by GTP-loading and cytosol to membrane translocation is regulated by p38 activity (El Bekay et al, 2007; Zuluaga et al, 2007; Osada et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation

Reed-Geaghan¹,

Savage²,

Hise³

et al. 2009

J. Neurosci.

499

415

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Microglia are the brain's tissue macrophages and are found in an activated state surrounding ␤-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar ␤-amyloid (fA␤) through an ensemble of surface receptors composed of the ␣ 6 ␤ 1 integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We report that the response of microglial cells to fibrillar forms of A␤ requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fA␤ is reliant upon CD14, which act together with TLR4 and TLR2 to bind fA␤ and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fA␤-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fA␤-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IB␣ following fA␤. These data indicate these innate immune receptors function as members of the microglial fA␤ receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation.

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“…However, the focal distribution of highly activated microglia / phagocytes within the molecular layer of the KO cerebellum rather suggests an exogenous activation of microglia rather than self-activation. In mouse models of GM1 and GM2 gangliosidoses, CNS inflammation is prominent and the reduction of these stored gangliosides decreased microglia activation in vivo (40), whereas mixed brain gangliosides and GM1 alone can induce microglia ramification in vitro (44), indicating that the amount of stored gangliosides in the brain is crucial for microglia activation possibly via toll-like receptors (45, 46). We therefore speculate that in α-mannosidosis mice, GM1 storage is the main factor stimulating microglia activation but our data suggest that both exogenous stimuli as well as endogenous storage likely contribute to the inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Cerebellar Alterations and Gait Defects as Therapeutic Outcome Measures for Enzyme Replacement Therapy in α-Mannosidosis

Damme

Walkley

Lüllmann‐Rauch

et al. 2011

J Neuropathol Exp Neurol

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α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy (ERT) that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term ERT partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures.

show abstract

GM1 induces p38 and microtubule dependent ramification of rat primary microglia in vitro

Cited by 18 publications

References 58 publications

Constitutive and functional expression of YB-1 in microglial cells

Constitutive and functional expression of YB-1 in microglial cells

CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation

Cerebellar Alterations and Gait Defects as Therapeutic Outcome Measures for Enzyme Replacement Therapy in α-Mannosidosis

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