Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and decrease its phagocytosis and degradation by microglial cells in culture

Bernhardi, Rommy von; Ramı́rez, Galo; Toro, Rodrigo; Eugenı́n, Jaime

doi:10.1016/j.nbd.2006.12.006

Cited by 42 publications

(31 citation statements)

References 99 publications

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“…However, reactivity of microglia and astrocytes against Ab can promote or exacerbate the neuropathological changes of AD [43,97]. In fact, inflammatory conditions can impair microglial capacity for internalization of amyloid precursor protein (APP) peptides [142] and affect the expression and function of APP secretases [116] favouring the accumulation of Ab fibrils. Similarly, microglia-derived IL-1b and IL-6 can induce tau hyperphosphorylation through activation of the p38-MAPK and cyclin-dependent kinase 5 (cdk5), respectively [73].…”

Section: Acute Systemic Inflammation In Dementiamentioning

confidence: 99%

The neuroinflammatory hypothesis of delirium

et al. 2010

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Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short-and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies.

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Section: Acute Systemic Inflammation In Dementiamentioning

confidence: 99%

The neuroinflammatory hypothesis of delirium

et al. 2010

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“…normally would fail to induce their activation such as APP or A , compounds that are not potent activators by themselves (von Bernhardi and Eugenín., 2004;von Bernhardi et al, 2007). Abnormal glial activation can also impair the capacity of glia to uptake and degrade A (Rogers et al, 2002).…”

Section: Glial Dysregulation Hypothesis In Admentioning

confidence: 99%

Glial cell dysregulation: a new perspective on Alzheimer disease

2007

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Alzheimer disease (AD) is a major cause of dementia. Several mechanisms have been postulated to explain its pathogenesis, beta-amyloid (A beta toxicity, cholinergic dysfunction, Tau hyper-phosphorylation, oxidative damage, synaptic dysfunction and inflammation secondary to senile plaques, among others. Glial cells are the major producers of inflammatory mediators, and cytotoxic activation of glial cells is linked to several neurodegenerative diseases; however, whether inflammation is a consequence or the cause of neurodegeneration is still unclear. I propose that inflammation and cellular stress associated with aging are key events in the development of AD through the induction of glial dysfunction. Dysregulated inflammatory response can elicit glial cell activation by compounds which are normally poorly reactive. Inflammation can also be the major cause of defective handling of A beta and the amyloid precursor protein (APP). Here I review evidence that support the proposal that dysfunctional glia and the resulting neuroinflammation can explain many features of AD. Evidence supports the notion that damage caused by inflammation is not only a primary cause of neurodegeneration but also an inducer for the accumulation of A beta in AD. Dysfunctional glia can result in impaired neuronal function in AD, as well as in many progressive neurodegenerative disorders. We show that microglial cell activation is enhanced under pro-inflammatory conditions, indicating that glial cell responses to A beta related proteins can be critically dependent on the priming of glial cells by pro-inflammatory factors.

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“…These changes were accompanied by the up-regulation of IL-1β, COX-2, and iNOS, which could be specific for the CA1 area, as they were not detected in the total hippocampal lysates. Human Alzheimer's disease and models are characterized by a high microglial hyperreactivity (1,3), which increases the release of proinflammatory cytokines and decreases βA clearance (4,22). For this reason, IL-1β stimulates the production of COX-2 by microglial cells in brains affected by Alzheimer's disease (23), which favors the expression of iNOS through PGE 2 production (24), although IL-1β also directly activates before iNOS (7).…”

Section: Discussionmentioning

confidence: 99%

Quercetin ameliorates inflammation in CA1 hippocampal region in aged triple transgenic Alzheimer´s disease mice model.

2017

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Introduction: Alzheimer's disease is the most common form of dementia. It is characterized by histopathological hallmarks such as senile plaques and neurofibrillary tangles, as well as a concomitant activation of microglial cells and astrocytes that release pro-inflammatory mediators such as IL-1β, iNOS, and COX-2, leading to neuronal dysfunction and death. Objective: To evaluate the effect of quercetin on the inflammatory response in the CA1 area of the hippocampus in a 3xTg-AD male and female mice model. Materials and methods: Animals were injected intraperitoneally with quercetin every 48 hours during three months, and we conducted histological and biochemical studies. Results: We found that in quercetin-treated 3xTg-AD mice, reactive microglia and fluorescence intensity of Aβ aggregates significantly decreased. GFAP, iNOS, and COX-2 immunoreactivity also decreased and we observed a clear tendency in the reduction of IL-1β in hippocampal lysates. Conclusion: Our work suggests an anti-inflammatory effect of quercetin in the CA1 hippocampal region of aged triple transgenic Alzheimer's disease mice.

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Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and decrease its phagocytosis and degradation by microglial cells in culture

Cited by 42 publications

References 99 publications

The neuroinflammatory hypothesis of delirium

The neuroinflammatory hypothesis of delirium

Glial cell dysregulation: a new perspective on Alzheimer disease

Quercetin ameliorates inflammation in CA1 hippocampal region in aged triple transgenic Alzheimer´s disease mice model.

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