The Innate Immunity in Alzheimer Disease- Relevance to Pathogenesis and Therapy

Błach-Olszewska, Z; Zaczyńska, Ewa; Gustaw-Rothenberg, Kasia; Avila-Rodrigues, Marco; Barreto, George E.; Leszek, Jerzy; Aliev, Gjumrakch

doi:10.2174/1381612821666150710144829

Cited by 24 publications

(11 citation statements)

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“…In parallel to NF-κB, the expression of iNOS and ROS was significantly decreased with the treatment of HS. Inflammatory mediators are thought to be vital in acute and chronic brain injury, such as stroke [45], Alzheimer’s disease [46] and Parkinson’s disease [47]. Excessive release of proinflammatory mediators can lead to neuronal death, glia activation, synaptic impairment and exacerbate neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Hypertonic saline attenuates expression of Notch signaling and proinflammatory mediators in activated microglia in experimentally induced cerebral ischemia and hypoxic BV-2 microglia

et al. 2017

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BackgroundIschemic stroke is a major disease that threatens human health in ageing population. Increasing evidence has shown that neuroinflammatory mediators play crucial roles in the pathophysiology of cerebral ischemia injury. Notch signaling is recognized as the cell fate signaling but recent evidence indicates that it may be involved in the inflammatory response in activated microglia in cerebral ischemia. Previous report in our group demonstrated hypertonic saline (HS) could reduce the release of interleukin-1 beta and tumor necrosis factor-alpha in activated microglia, but the underlying molecular and cellular mechanisms have remained uncertain. This study was aimed to explore whether HS would partake in regulating production of proinflammatory mediators through Notch signaling.ResultsHS markedly attenuated the expression of Notch-1, NICD, RBP-JK and Hes-1 in activated microglia both in vivo and in vitro. Remarkably, HS also reduced the expression of iNOS in vivo, while the in vitro levels of inflammatory mediators Phos-NF-κB, iNOS and ROS were reduced by HS as well.ConclusionOur results suggest that HS may suppress of inflammatory mediators following ischemia/hypoxic through the Notch signaling which operates synergistically with NF-κB pathway in activated microglia. Our study has provided the morphological and biochemical evidence that HS can attenuate inflammation reaction and can be neuroprotective in cerebral ischemia, thus supporting the use of hypertonic saline by clinicians in patients with an ischemia stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0351-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Hypertonic saline attenuates expression of Notch signaling and proinflammatory mediators in activated microglia in experimentally induced cerebral ischemia and hypoxic BV-2 microglia

et al. 2017

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“…The enhanced neuroinflammatory process damages neurons and alters the (BBB). These mediators also induce peripheral inflammation and then return to further stimulate local neuroinflammation ( Blach-Olszewska et al, 2015 ; Festoff, 2016 ; Busse et al, 2017 ). This progressive pro-inflammatory situation is exacerbated with age, creating a vicious cycle of local and systemic inflammatory responses leading to activation of cytotoxic microglia, unbalanced cytokine production, Aβ accumulation and irreversible brain damage.…”

Section: How May All These Theories Be Reconciled?mentioning

confidence: 99%

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer’s Disease?

Fülöp

Witkowski

Bourgade

et al. 2018

Front. Aging Neurosci.

159

125

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Alzheimer’s disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the “beta-amyloid hypothesis” that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the “infection hypothesis” was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection – Aβ – AD and discuss future possible treatments based on this paradigm.

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“…In AD, neuroinflammation is a significant contributor to disease progression [63]. Aβ accumulation causes excessive activation of astrocytes and increases transcription and protein levels of inflammatory factors [64], while the occurrence of inflammation could further aggravate tau phosphorylation. NSAIDs (nonsteroidal anti-inflammatory drugs) have been shown to be effective in ameliorating AD symptoms [65].…”

Section: Discussionmentioning

confidence: 99%

Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice

et al. 2019

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The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of β-amyloid (Aβ) plaque and formation of neurofibrillary tangles in the brain. Recent evidence shows that autophagy activation may potently promote intracellular Aβ clearance. Thus targeting autophagy becomes a promising strategy for discovery of drug leads against AD. In the present study, we established a platform to discover autophagy stimulator and screened the lab in-house FDA-approved drug library. We found that anti-parasitic drug nitazoxanide (NTZ) was an autophagy activator and could efficiently improve learning and memory impairments in APP/PS1 transgenic mice. In BV2 cells and primary cortical astrocytes, NTZ stimulated autophagy and promoted Aβ clearance by inhibiting both PI3K/AKT/mTOR/ULK1 and NQO1/mTOR/ULK1 signaling pathways; NTZ treatment attenuated LPS-induced inflammation by inhibiting PI3K/AKT/IκB/NFκB signaling. In SH-SY5Y cells and primary cortical neurons, NTZ treatment restrained tau hyperphosphorylation through inhibition of PI3K/AKT/GSK3β pathway. The beneficial effects and related signaling mechanisms from the in vitro studies were also observed in APP/PS1 transgenic mice following administration of NTZ (90 mg•kg −1 •d −1 , ig) for 100 days. Furthermore, NTZ administration decreased Aβ level and senile plaque formation in the hippocampus and cerebral cortex of APP/PS1 transgenic mice, and improved learning and memory impairments in Morris water maze assay. In conclusion, our results highlight the potential of NTZ in the treatment of AD.

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The Innate Immunity in Alzheimer Disease- Relevance to Pathogenesis and Therapy

Cited by 24 publications

References 0 publications

Hypertonic saline attenuates expression of Notch signaling and proinflammatory mediators in activated microglia in experimentally induced cerebral ischemia and hypoxic BV-2 microglia

Hypertonic saline attenuates expression of Notch signaling and proinflammatory mediators in activated microglia in experimentally induced cerebral ischemia and hypoxic BV-2 microglia

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer’s Disease?

Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice

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