Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease

Sep 15, 2020Neurochemical research

How NLRP3 Inflammasome Activation May Influence Alzheimer's Disease Treatment

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Abstract

Microglia-specific NLRP3 inflammasome activation is associated with Aβ deposition and neuronal loss in a mouse model of Alzheimer's disease.

NLRP3 inflammasome-mediated chronic neuroinflammation plays a crucial role in the development of Alzheimer's disease.
Aβ deposition stimulates NLRP3 assembly and activation in microglia, leading to inflammatory responses.
Activated NLRP3 in microglia promotes the expression of inflammatory markers such as caspase-1 and IL-1β.
Deletion of NLRP3 or caspase-1 in Alzheimer’s mouse models promotes an anti-inflammatory microglial phenotype.
This anti-inflammatory shift is linked to improved cognitive function, enhanced Aβ clearance, and reduced brain inflammation.

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Alzheimer's disease (AD) is a common neurodegenerative disease of progressive dementia which is characterized pathologically by extracellular neuritic plaques containing aggregated amyloid beta (Aβ) and intracellular hyperphosphorylated tau protein tangles in cerebrum. It has been confirmed that microglia-specific nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated chronic neuroinflammation plays a crucial role in the pathogenesis of AD. Stimulated by Aβ deposition, NLRP3 assembles and activates within microglia in the AD brain, leading to caspase-1 activation along with downstream interleukin (IL)-1β secretion, and subsequent inflammatory events. Activation of the NLRP3 inflammasome mediates microglia to exhibit inflammatory M1 phenotype, with high expression of caspase-1 and IL-1β. This leads to Aβ deposition and neuronal loss in the amyloid precursor protein (APP)/human presenilin-1 (PS1) mouse model of AD. However, NLRP3 or caspase-1 deletion in APP/PS1 mice promotes microglia to transform to an anti-inflammatory M2 phenotype, with decreased secretion of caspase-1 and IL-1β. It also results in improved cognition, enhanced Aβ clearance, and a lower cerebral inflammatory response. This result suggests that the NLRP3 inflammasome may be an appropriate target for reducing neuroinflammation and alleviating pathological processes in AD. In the present review, we summarize the generally accepted regulatory mechanisms of NLRP3 inflammasome activation, and explore its role in neuroinflammation. Furthermore, we speculate on the possible roles of microglia-specific NLRP3 activation in AD pathogenesis and consider potential therapeutic interventions targeting the NLRP3 inflammasome in AD.

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Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease

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