The Role of Neuronal NLRP1 Inflammasome in Alzheimer’s Disease: Bringing Neurons into the Neuroinflammation Game

Abstract

The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β and interleukin-18 (IL-1β and IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation also induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the NLRP1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD.

NLRP1-Mediated Antidepressant Effect of Ketamine in Chronic Unpredictable Mild Stress Model in Rats

“…NLRP1 is primarily expressed by neurons and oligodendrocytes and its activation cleaves caspase-1 into its active subunits thereby eliciting IL-1β and IL-18 production. 23,24 Establishment of the CUMS model in rats resulted in enhanced NLRP1 expression in the prefrontal cortex, as reported previously. 14 Acute and chronic ketamine administration reduced expression levels of both NLRP1 and other components of the inflammasome complex, caspase-1 and ASC.…”

“…Our results also suggest that neurons might as well partake in neuro-inflammation aspects of MDD, as proposed previously. 23 NF-κB is known to play an important role in the physiopathology of depression by enhancing the transcription of proinflammatory cytokines. 27 Ketamine has been found to inhibit lipopolysaccharide (LPS)-induced NF-κB activation in astrocytes, human glioma cells and mouse brain cells.…”

The NLRP1 Inflammasome in Human Skin and Beyond

“…Furthermore, in the absence of caspase-1, NLRP1 can induce apoptosis requiring expression of ASC and caspase-8 [91]. NLRP1 is broadly expressed but at particularly high levels by neurons [92] and, interestingly, by differentiated epithelial cells, such as epidermal keratinocytes [88].…”

Functional Gene Trap Mutagenesis Screen for Genes and Molecular Mechanisms Underlying Amyloid-β-induced Inflammasome-mediated Neuronal Death

“…Recently, studies on the innate immunity within the central nervous system (CNS) is beginning to gain traction as neuroin ammation becomes widely suspected as the missing link between the two pathological hallmarks of AD (amyloid-β (Aβ) and neuro brillary tangles) and neuronal death [2]. In particular, the regulatory molecules of in ammation known as in ammasomes could be responsible for neuroin ammation in AD as they enable an immune response against AD pathologies in both microglia and in neurons [3,4]. The activation of in ammasomes results in caspase-1 mediated pyroptosis, a form of autolytic cell death characterised by the rupture of cell membrane followed by the release of pro-in ammatory cytokines [5].…”