Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia

Sondag, Cindy; Dhawan, Gunjan; Combs, Colin K.

doi:10.1186/1742-2094-6-1

Cited by 214 publications

(162 citation statements)

References 66 publications

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“…Pharmacological inhibitors of Syk have been developed and represent potential immunomodulatory agents for the treatment of autoimmune and inflammatory conditions. Interestingly, A␤ has been shown to stimulate Syk activity resulting in microglial activation and neurotoxicity (65)(66)(67)(68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Paris

Ait‐Ghezala

Bachmeier

et al. 2014

Journal of Biological Chemistry

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Background: Spleen tyrosine kinase (Syk) mediates microglial activation and neurotoxicity elicited by Alzheimer A␤ peptides. Results: Syk regulates A␤ production via NFB-dependent mechanisms and Tau phosphorylation by controlling the activation of glycogen synthase 3␤. Conclusion: Inhibition of Syk can interrupt the neuroinflammation, pathological A␤ accumulation, and Tau hyperphosphorylation in AD. Significance: Syk represents a therapeutic target for the key pathological lesions that define AD.

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Section: Discussionmentioning

confidence: 99%

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Paris

Ait‐Ghezala

Bachmeier

et al. 2014

Journal of Biological Chemistry

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“…Recent studies have shown that the soluble assemblies of Aβ also stimulate neuronal dysfunction and may play a prominent role in stimulating the proinflammatory activation of primary microglia [247] . In the context of inflammation, compared to fibrillar assemblies, oligomer Aβ preparations induce greater or differential proinflammatory cytokine production by microglia and astrocytes in vitro [248] .…”

Section: Aβ and Inflammationmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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“…Indeed, activated microglial cells located in close proximity to Ab plaques are found in patients with AD (9) and transgenic mouse models of AD (10). Moreover, it has been shown that Ab peptide itself provokes activation of microglia, stimulating critical signaling responses that lead to increased IL-6 production, inducing the death of cultured neurons (11). In addition, Ab peptide was shown to enhance the action of TLR2 and 4 agonists in primary mouse microglial cells (12), suggesting a role of the TLRs in mediating Ab -driven inflammatory responses.…”

mentioning

confidence: 99%

Active Immunization with Amyloid-β 1–42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System

Vollmar

Kullmann

Thilo

et al. 2010

The Journal of Immunology

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Active immunization with amyloid-β (Aβ) peptide 1–42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer’s disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Aβ1–42 are poorly understood. In this study, we characterized cognitive and immunological consequences of Aβ1–42/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)35–55/CFA or CFA alone, Aβ1–42/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aβ1–42/CFA-immunized animals. In contrast to MOG35–55/CFA and PBS/CFA controls, the majority of infiltrating cells in Aβ1–42/CFA-immunized mice were CD11b+CD14+ and CD45high, indicating their blood-borne monocyte/macrophage origin. Immunization with Aβ1–42/CFA was significantly more potent than immunization with MOG35–55/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aβ1–42-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aβ1–42/CFA. Thus, this study identifies adjuvant effects of Aβ1–42, which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aβ immunotherapy.

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Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia

Cited by 214 publications

References 66 publications

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation

Amyloid beta: structure, biology and structure-based therapeutic development

Active Immunization with Amyloid-β 1–42 Impairs Memory Performance through TLR2/4-Dependent Activation of the Innate Immune System

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