Inhibition of phagocytosis reduced the classical activation of BV2 microglia induced by amyloidogenic fragments of beta-amyloid and prion proteins

Abstract

The inflammatory responses in Alzheimer's disease and prion diseases are dominated by microglia activation. Three different phenotypes of microglial activation, namely classical activation, alternative activation, and acquired deactivation, have been described. In this study, we investigated the effect of amyloidogenic fragments of amyloid b and prion proteins (Ab 1-42 and PrP 106-126 ) on various forms of microglial activation. We first examined the effect of Ab 1-42 and PrP 106-126 stimulation on the mRNA expression levels of several markers of microglial activation, as well as the effect of cytochalasin D, a phagocytosis inhibitor, on microglial activation in Ab 1-42 -and PrP 106-126 -stimulated BV2 microglia. Results showed that Ab 1-42 and PrP 106-126 induced the classical activation of BV2 microglia, decreased the expression level of alternative expression markers, and had no effect on the expression of acquired deactivation markers. Cytochalasin D treatment significantly reduced Ab 1-42 -and PrP 106-126 -induced up-regulation of proinflammatory factors, but did not change the expression profile of the markers of alternative activation or acquired deactivation in BV2 cells which were exposed to Ab 1-42 and PrP 106-126 . Our results suggested that microglia interact with amyloidogenic peptides in the extracellular milieu-stimulated microglial classical activation and reduce its alternative activation, and that the uptake of amyloidogenic peptides from the extracellular milieu amplifies the classical microglial activation.

NALP3 inflammasome activation in protein misfolding diseases

“…Furthermore, NALP3 or caspase-1 deficiency resulted in a skew of microglia activation towards an M-2 like activated state, as markers of alternative activation of microglia of the M2 type such as "found in inflammatory zone 1 (FIZZ1)" and arginase-1 are upregulated, and hallmark of classical activation M1 type-NOS2 are downregulated [22]. This is consistent with our previous study which demonstrated that inhibition of NALP3 inflammasome by Cytochalasin D reduced classical activation of microglia upon exposure to Aβ and PrP fibrils [61,62]. It has been proved that activation of NALP3 inflammasome induced M1 type Fig.…”

“…Then, the activation of NALP3 inflammasome leads to caspase-1 activation and IL-1β release. activation of microglia and resulted in the clearance of Aβ, but activation of M2 type of microglia could ultimately reduce Aβ deposition and protect against synaptic dysfunction [62].…”

The Role of Inflammasomes in the Pathogenesis of Neurodegenerative Diseases

“…This is consistent with the results of another study showing that inhibition of the NLRP3 inflammasome by cytochalasin D reduces classical microglial activation upon exposure to Aβ [ 55 ]. Activation of the NLRP3 inflammasome was shown to induce the acquisition of a pro-inflammatory M1 phenotype by microglia and lead to clearance of Aβ; in the case of the M2 phenotype, Aβ deposition decreases and favorable conditions for synaptogenesis are created [ 56 ].…”