Interleukin-1β mediated amyloid plaque clearance is independent of CCR2 signaling in the APP/PS1 mouse model of Alzheimer's disease

Abstract

Neuroinflammation is a key component of Alzheimer’s disease (AD) pathogenesis. Particularly, the proinflammatory cytokine interleukin-1 beta (IL-1β) is upregulated in human AD and believed to promote amyloid plaque deposition. However, studies from our laboratory have shown that chronic IL-1β overexpression in the APPswe/PSEN1dE9 (APP/PS1) mouse model of AD ameliorates amyloid pathology, increases plaque-associated microglia, and induces recruitment of peripheral immune cells to the brain parenchyma. To investigate the contribution of CCR2 signaling in IL-1β-mediated amyloid plaque clearance, seven month-old APP/PS1/CCR2-/- mice were intrahippocampally transduced with a recombinant adeno-associated virus serotype 2 containing the cleaved form of human IL-1β (rAAV2-IL-1β). Four weeks after rAAV2-IL-1β transduction, we found significant reductions in 6E10 and Congo Red staining of amyloid plaques that was confirmed by decreased levels of insoluble Aβ1-42 and Aβ1-40 in the inflamed hippocampus. Bone marrow chimeric studies confirmed the presence of infiltrating immune cells following IL-1β overexpression and revealed that dramatic reduction of CCR2+ peripheral mononuclear cell recruitment to the inflamed hippocampus did not prevent the ability of IL-1β to induce amyloid plaque clearance. These results suggest that infiltrating CCR2+ monocytes do not contribute to IL-1β-mediated amyloid plaque clearance.

The role of NLRP3-CASP1 in inflammasome-mediated neuroinflammation and autophagy dysfunction in manganese-induced, hippocampal-dependent impairment of learning and memory ability

“…17 Therefore, we explored whether the increase of CTSB was involved in Mn-induced activation of the NLRP3 inflammasome. NH 4 Cl inhibits the acidification of the lysosome and decreases the expression of CTSB. 50 We found that NH 4 Cl significantly inhibited the Mn-induced increase of CTSB, NLRP3 and cleaved CASP1, and the release of IL1B and IL18, without a significant effect on autophagy-related proteins.…”

“…< P < 0.05 when compared with the Nlrp3 siRNA Group. the NH 4 Cl caused a significant reduction in protein CTSB levels, attenuating the activation of NLRP3-CASP1 inflammasomes (Fig. 10A, B) as well as the release of IL1B and IL18 (Fig.…”

“…5B). To further examine whether release of CTSB from the lysosomes was involved in the activation of the NLRP3-CASP1 inflammasome pathway, BV2 cells were treated with 20 mM NH 4 Cl to suppress the activities of CTSB via shifting the lysosomal pH above the optimum of their activities. Treatment with Statistical analysis was performed with one-way ANOVA.…”

“…IL1B levels are elevated in AD, contributing to its pathology by increasing amyloid precursor gene expression, MAPT/Tau hyperphosphorylation and memory impairment. 4 Manganese (Mn) is an essential trace element that is widely distributed in the earth crust. It not only plays a key role in numerous biochemical reactions, including immune response, ATP generation, bone growth, digestion and reproduction, but also serves as a cofactor for various enzymes, such as arginase and glutamine synthetase.…”

Application of APP/PS1 Transgenic Mouse Model for Alzheimer’s Disease

“…Chemokine ligand 4(CCL4) is overexpressed in APP/PS1 brains and that levels of CCL4 mRNA and protein are positively correlated with the age-related progression of cerebral insoluble Aβ deposition in these mice [48]. Other studies showed that long term over-expression of IL-1β could improve the pathological changes of Aβ, increase the expression of microglia associated with Aβ plagues, and induce the entry of peripheral immune cells into the brain [49].…”