Microglial Activation in Alzheimers Disease

Schlachetzki, J; Hüll, Michael

doi:10.2174/156720509790147179

Cited by 77 publications

(62 citation statements)

References 112 publications

(112 reference statements)

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“…Other responses, such as chronic inflammatory response, are also unique to the Glud1 Tg mouse model. Because chronic inflammation is an important aspect of brain aging and many neurodegenerative conditions [92-94], these responses in Glud1 Tg mice make this mouse a more useful model of chronic brain neurodegenerative conditions than the acute Glu treatment models of neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

et al. 2010

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BackgroundIncreases during aging in extracellular levels of glutamate (Glu), the major excitatory neurotransmitter in the brain, may be linked to chronic neurodegenerative diseases. Little is known about the molecular responses of neurons to chronic, moderate increases in Glu levels. Genome-wide gene expression in brain hippocampus was examined in a unique transgenic (Tg) mouse model that exhibits moderate Glu hyperactivity throughout the lifespan, the neuronal Glutamate dehydrogenase (Glud1) mouse, and littermate 9 month-old wild type mice.ResultsIntegrated bioinformatic analyses on transcriptomic data were used to identify bio-functions, pathways and gene networks underlying neuronal responses to increased Glu synaptic release. Bio-functions and pathways up-regulated in Tg mice were those associated with oxidative stress, cell injury, inflammation, nervous system development, neuronal growth, and synaptic transmission. Increased gene expression in these functions and pathways indicated apparent compensatory responses offering protection against stress, promoting growth of neuronal processes (neurites) and re-establishment of synapses. The transcription of a key gene in the neurite growth network, the kinase Ptk2b, was significantly up-regulated in Tg mice as was the activated (phosphorylated) form of the protein. In addition to genes related to neurite growth and synaptic development, those associated with neuronal vesicle trafficking in the Huntington's disease signalling pathway, were also up-regulated.ConclusionsThis is the first study attempting to define neuronal gene expression patterns in response to chronic, endogenous Glu hyperactivity at brain synapses. The patterns observed were characterized by a combination of responses to stress and stimulation of nerve growth, intracellular transport and recovery.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

et al. 2010

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“…These aggregates are often surrounded by activated microglial cells, the resident macrophage-like cells of the brain [1-3] and, in vitro aggregated forms of disease-associated peptides stimulate cytokine secretion from microglia/macrophages [3-6]. Numerous studies suggest that cytokine-induced neuroinflammation contributes to the clinical progression of AD, PD and prion diseases [7-9].…”

Section: Introductionmentioning

confidence: 99%

Glimepiride reduces CD14 expression and cytokine secretion from macrophages

Ingham

Williams

Bate

2014

J Neuroinflammation

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BackgroundActivated microglia are associated with deposits of aggregated proteins within the brains of patients with Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases. Since the cytokines secreted from activated microglia are thought to contribute to the pathogenesis of these neurodegenerative diseases, compounds that suppress cytokine production have been identified as potential therapeutic targets. CD14 is a glycosylphosphatidylinositol (GPI)- anchored protein that is part of a receptor complex that mediates microglial responses to peptides that accumulate in prion disease (PrP82-146), AD (amyloid-β (Aβ)42) and PD (α-synuclein (αSN)). As some GPI-anchored proteins are released from cells by treatment with glimepiride, a sulphonylurea used for the treatment of diabetes, the effects of glimepiride upon CD14 expression and cytokine production from cultured macrophages were studied.MethodsRAW 264 cells and microglial cells were treated with glimepiride or phosphatidylinositol (PI)-phospholipase C (PLC) and the expression of cell receptors was analysed by ELISA and immunoblot. Treated cells were subsequently incubated with Aβ42, αSN, PrP82-146 or lipopolysaccharide (LPS) and the amounts of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6 measured.ResultsGlimepiride released CD14 from RAW 264 cells and microglial cells. Pre-treatment with glimepiride significantly reduced TNF, IL-1 and IL-6 secretion from RAW 264 and microglial cells incubated with LPS, Aβ42, αSN and PrP82-146. Glimepiride also reduced the LPS, Aβ42, αSN and PrP82-146-induced translocation of TLR-4 into membrane rafts that is associated with cell activation. These effects of glimepiride were also seen after digestion of RAW 264 cells with PI-phospholipase C (PLC). In addition, the effects of glimepiride were blocked by pharmacological inhibition of GPI-PLC. The cytokine production was CD14-dependent; it was reduced in microglia from CD14 knockout mice and was blocked by antiserum to CD14.ConclusionsRAW 264 and microglial cell responses to Aβ1–42, αSN, PrP82-146 and LPS are dependent upon CD14 expression. Glimepiride induced the shedding of CD14 from cells by activation of GPI-PLC and consequently reduced cytokine production in response to Aβ42, αSN, PrP82-146 and LPS. These results suggest that glimepiride acts as a novel anti-inflammatory agent that could modify the progression of neurodegenerative diseases.

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“…More recently, reprogramming of AD patient-derived non-neuronal somatic cells into neuronal mature cells (iNCs) [98,103], AD patientderived olfactory mucosa stem cells [96], genetically modified human neural stem cells (NSCs) [19], and three-dimensional culture systems [104] have been applied. Additionally, microglial cells, known to get activated in AD [105], have been derived from elderly patients to define the role of active microglia in the inflammatory process characterizing AD [106], and can be applied in co-culture systems to complement hiPSC, iNC, and NSC cultures. Moreover, novel brain-on-a-chip systems are currently under development, ideally leading to the design of novel drugs in human-based systems [107,108].…”

Section: The Organ/tissue and Cellular Levels: Novel Human Stem Cell mentioning

confidence: 99%

A Human-Based Integrated Framework forAlzheimer’s Disease Research

Pistollato

Cavanaugh

Chandrasekera

2015

JAD

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Abstract. Animal models of Alzheimer's disease (AD) have been extensively utilized for decades in an effort to elucidate the pathophysiological mechanisms of this disease and to test novel therapeutic approaches. However, research success has not effectively translated into therapeutic success for human patients. This translational failure is partially due to the overuse of animal models that cannot accurately recapitulate human AD etiopathogenesis or drug responses and the inadequate use of human-relevant research methods. Here, we propose how to mitigate this translational barrier by employing human-based methods to elucidate disease processes occurring at multiple levels of complexity, accounting for gene and protein expression and the impact of disease at the cellular, tissue/organ, individual, and population levels. In particular, novel human-based cellular and computational models, together with epidemiological and clinical studies, represent the ideal tools to facilitate human-relevant data acquisition, in the effort to better elucidate AD pathogenesis in a human-based setting and design more effective treatments and preventive strategies. Our analysis indicates that a paradigm shift toward human-based, rather than animal-based research is required in the face of the ever-increasing prevalence of AD in the 21st century.

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Microglial Activation in Alzheimers Disease

Cited by 77 publications

References 112 publications

Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

Transcriptomic responses in mouse brain exposed to chronic excess of the neurotransmitter glutamate

Glimepiride reduces CD14 expression and cytokine secretion from macrophages

A Human-Based Integrated Framework forAlzheimer’s Disease Research

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