IKKβ Deficiency in Myeloid Cells Ameliorates Alzheimer's Disease-Related Symptoms and Pathology

Abstract

Alzheimer's disease (AD) is characterized by extracellular amyloid-␤ (A␤) deposits and microglia-dominated inflammatory activation.Innate immune signaling controls microglial inflammatory activities and A␤ clearance. However, studies examining innate immunity in A␤ pathology and neuronal degeneration have produced conflicting results. In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKK␤, specifically in the myeloid cells of TgCRND8 APP-transgenic mice. Deficiency of IKK␤ in myeloid cells, especially microglia, simultaneously reduced inflammatory activation and A␤ load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKK␤ deficiency enhanced microglial recruitment to A␤ deposits and facilitated A␤ internalization, perhaps by inhibiting TGF-␤-SMAD2/3 signaling, but did not affect A␤ production and efflux. Therefore, inhibition of IKK␤ signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing A␤ clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression.

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

“…All images were acquired by Zeiss AxioImager.Z2 microscope equipped with a Stereo Investigator system (MBF Bioscience, Williston). In the whole hippocampus and cortex, volumes of A␤ and brain tissues were estimated with the Cavalieri probe as we described in the previous study (30) with a 15-m grid size, which provided coefficient of error estimates of Ͻ0.05. The A␤ load was demonstrated as the ratio of A␤ volume to relevant brain tissue volume.…”

“…Interestingly, the histological analysis using the stereological Cavalieri method (30) revealed that heterozygous deletion of p38␣ MAPK in neurons resulted in strongly reduced A␤ levels in both the hippocampus and cortex of APP-transgenic mice, even as early as 4 months of age (APP tg p38 fl/wt Nex-Cre fl/fl Nex-Cre Ϫ/Ϫ , but without the expression of human APP. We observed that neuronal p38␣ MAPK deletion significantly reduced the activity of ␤-secretase, but not of ␥-secretase, in a copy-dependent manner (Fig.…”

Stimulation of TLR4 Attenuates Alzheimer’s Disease–Related Symptoms and Pathology in Tau-Transgenic Mice

“…C57BL/6J mice were originally imported from Charles River Laboratories and bred in our animal facilities. To establish mice with modified inflammatory activation specifically in myeloid cells, we cross-bred ikbkb fl/fl (24), MyD88 fl/fl (25), or p38a fl/fl (26) mice with LysM-Cre knock-in mice expressing Cre from the endogenous lysozyme 2 gene locus (27) as we did previously (9) LysM-Cre +/2 mice, respectively, and their effects on inflammatory responses in mice have been previously described (28)(29)(30). To estimate the efficiency of LysMCre-mediated gene recombination of floxed ikbkb, myd88, and p38a-mapk genes in myeloid cells, we cross-bred LysM-Cre mice to ROSA mT/mG Cre reporter mice (The Jackson Laboratory, stock no.…”

“…Aggregated Ab activates microglia through CD14/TLR2/TLR4-MyD88-kinase of NF-kB inhibitor (IKK) b signaling pathway (6)(7)(8)(9)(10). In p-Tau-induced AD pathogenesis, inflammatory activation might serve as a two-edged sword: on one side, certain inflammatory cytokines, such as IL-1b, promote phosphorylation and aggregation of Tau by activating p38a-MAPK in neurons (11)(12)(13).…”

The Nogo/Nogo Receptor (NgR) Signal Is Involved in Neuroinflammation through the Regulation of Microglial Inflammatory Activation

“…It is well established that NF-B and STAT3 are transcription factors that participate in cytokine and growth factor actions in immune cells and transcription of a variety of genes involved in inflammation, cellular adaptation to stress, and cell death (36). Activated IKK␤ phosphorylates IB and triggers its degradation by proteasomes, and this process results in translocation of NF-B to the nucleus and the induction of NF-B-dependent transcription of a wide range of immune and inflammatory genes (37). Recently, research has found that the NF-B signal pathway is central to many macrophage (25) and microglial functions, including phagocytosis and cytokine secretion.…”