Abstract
Alzheimer’s disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. The typical pathological characteristics of AD are extracellular senile plaques composed of amyloid ß (Aβ) protein, intracellular neurofibrillary tangles formed by the hyperphosphorylation of the microtubule-associated protein tau, and neuron loss. In the past hundred years, although human beings have invested a lot of manpower, material and financial resources, there is no widely recognized drug for the effective prevention and clinical cure of AD in the world so far. Therefore, evaluating and exploring new drug targets for AD treatment is an important topic. At present, researchers have not stopped exploring the pathogenesis of AD, and the views on the pathogenic factors of AD are constantly changing. Multiple evidence have confirmed that chronic neuroinflammation plays a crucial role in the pathogenesis of AD. In the field of neuroinflammation, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a key molecular link in the AD neuroinflammatory pathway. Under the stimulation of Aβ oligomers and tau aggregates, it can lead to the assembly and activation of NLRP3 inflammasome in microglia and astrocytes in the brain, thereby causing caspase-1 activation and the secretion of IL-1β and IL-18, which ultimately triggers the pathophysiological changes and cognitive decline of AD. In this review, we summarize current literatures on the activation of NLRP3 inflammasome and activation-related regulation mechanisms, and discuss its possible roles in the pathogenesis of AD. Moreover, focusing on the NLRP3 inflammasome and combining with the upstream and downstream signaling pathway-related molecules of NLRP3 inflammasome as targets, we review the pharmacologically related targets and various methods to alleviate neuroinflammation by regulating the activation of NLRP3 inflammasome, which provides new ideas for the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative disease that occurs in the elderly, and is called senile dementia
More and more evidences have confirmed that nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation plays an important role in the pathogenesis and progression of AD
Microglia and astrocytes play a crucial role in the chronic neuroinflammatory response of AD caused by NLRP3 inflammasome
Summary
Alzheimer’s disease (AD) is a common neurodegenerative disease that occurs in the elderly, and is called senile dementia. Just like the structure of the abovementioned inflammasomes, the NLRP3 inflammasome includes the sensor protein NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (caspase activation and recruitment domain) (ASC), and the effector protein (pro-caspase-1, a cysteine protease) (Schroder and Tschopp 2010). These three proteins can interact closely to regulate the function of NLRP3 inflammasome. Under the stimulation of Aβ plaques and tau aggregates, microglia and astrocytes mediate chronic neuroinflammatory response, neuronal death and pyroptosis through intracellular NLRP3 inflammasome, thereby driving the occurrence and progression of AD (Han et al, 2020b; Van Zeller et al, 2021). We introduce the upstream and downstream signaling pathways of the NLRP3 inflammasome, as well as the latest developments regarding its potential targets and therapeutic strategies for AD treatment
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