The NALP3 inflammasome is involved in the innate immune response to amyloid-β

In the citing paper

“Based on the previous literature42,43,46, we reasoned that cathepsin B leaking from the destabilized lysosomes may mediate the NLRP3 inflammasome activation upon SHIP1 inhibition11.”

In the citing paper

“Fibrillar Aβ (fAβ), following phagocytosis by microglia, activates the NLRP3 inflammasome and leads to increases in secretion of IL-1β and IL-18.”

In the citing paper

“Sustained elevations of IL-1β have been postulated to play a key role in AD pathogenesis [6, 12–14].”

In the citing paper

“Halle et al. found that fibrillar Aβ can induce the secretion of IL-1β which depends on the presence of NLRP3.352,353”

In the citing paper

“lysosomal cathepsins, such as cathepsin B, can induce NLRP3 inflammasome activation upon leaking into the cytosol following lysosomal membrane permeabilization (LMP)42,43”

In the citing paper

“fAβ phagocytosis results in lysosomal dysfunction and release of lysosomal contents into the cytoplasm, including the lysosomal protease cathepsin B, which is a mediator of inflammasome activation induced by Aβ [78].”

In the citing paper

“In line with these findings, another study showed that aggregated tau seeds activated the NLRP3 inflammasome in primary mouse microglia by inducing lysosomal destabilization and release of the lysosomal protease cathepsin B, similar to fAβ [78, 82].”

In the citing paper

“In parallel, reduction of SHIP1 activity is poised to disinhibit signaling pathways that are involved in the phagocytosis of Aβ, which is a required step for Aβ-induced activation of the NLRP3 inflammasome [78].”

In the citing paper

“Notably, Aβ also can activate NF-κB signaling and the NLRP3-ASC inflammasome [426, 427], suggesting that Aβ and tau share common mechanisms in microglia activation.”

In the citing paper

“Following phagocytosis by microglia, Aβ activates the NLRP3 inflammasome leading to caspase-1 activation and IL-1β maturation and release (Halle et al., 2008).”

In the citing paper

“Fibrillar Aβ amyloids can induce the secretion of IL-1β from microglia, via the NLRP3 inflammasome (228, 249).”

In the citing paper

“Importantly, researchers also found that ASC-, caspase-1-, IL-1 receptor-, and MyD88-deficient mice had less recruitment of microglia and mononuclear phagocytes to Aβ in the brain as compared to the wild type control after the injection of Aβ into the striatum (228).”

In the citing paper

“NLRP3 has been shown to respond to sterile stimuli, including asbestos, silica, MSU and CPPD crystals55, cholesterol crystals and β-amyloid fibrils56.”

In the citing paper

“Furthermore, there is only partial inhibition of the neutrophil infiltration and IL-1β production associated with sterile inflammation in response to cholesterol crystals44,56,59,67.”

In the citing paper

“However, cathepsin b-deficient macrophages have no impairment in IL-1β production in response to certain NLRP3 agonists, including LPS plus ATP, or MSU crystals, despite the impairment in their response to silica44,56,59,67.”

In the citing paper

“evidence to support this are the observations that artificial lysosomal rupture alone can activate NLRP3 and that pharmacological inhibition or genetic depletion of cathepsin b results in inhibition of caspase 1 activation, although this inhibition was only partial44,56,59.”

In the citing paper

“In support of this, direct treatment of ATP on primed microglia is sufficient for maturation and release of IL-1β in vitro (Halle et al, 2008) and does so via the P2X 7 receptor (Colomar et al, 2003) expressed on microglia (Monif et al, 2009).”

In the citing paper

“In particular, microglial NLRP3 has been shown to be a major driver of amyloid beta and tau toxicity in AD, suggesting its activation has important implications for disease progression (Halle et al, 2008; Venegas et al, 2017; Ising et al, 2019).”