CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway

Fujikura, Mai; Iwahara, Naotoshi; Hisahara, Shin; Kawamata, Jun; Matsumura, Akihiro; Yokokawa, Kazuki; Saito, Taro; Manabe, Tatsuo; Matsushita, T.; Suzuki, Syuuichirou; Shimohama, Shun

doi:10.3233/jad-180904

Cited by 21 publications

(18 citation statements)

References 47 publications

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“…There are several mechanisms by which microglia take up various forms of A␤ into the cells, such as phagocytosis, receptor-mediated endocytosis, and pinocytosis [53,54]. We previously reported that receptor-mediated endocytosis of A␤ through the TLR4/CD14 complex, which is known to be a mediator of A␤-induced inflammation, is involved in the uptake of fibrillar A␤ by microglia, indicating that microglial CD14 is an important receptor for internalization of A␤ [16]. Because mutation of TLR4 increased soluble A␤ in a mouse model of AD [55] and knockdown of CD14 reduced uptake of monomeric A␤ in vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that microglial CD14 was an important receptor for A␤ uptake [16]. Therefore, we examined microglial CD14 expression in APdE9-MSC mice.…”

Section: Msc Transplantation Upregulated Microglial Cd14 Expressionmentioning

confidence: 95%

“…Monomeric, oligomeric and fibrillar A␤ 42 were prepared as described previously with minor modification [16,34]. For monomeric A␤ 42 preparations, HiLyte™ Fluor 488 or 633-labeled human synthetic A␤ 1-42 (A␤-488 or -633) and non-labeled A␤ 1-42 (Ana Spec, CA, USA) were suspended to 1 mM in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP; Sigma Aldrich, MO, USA) and lyophilized.…”

Section: Preparation Of Aβ 1-42mentioning

confidence: 99%

“…Peptide films were re-suspended to 5 mM in DMSO and sonicated for 30 min, then diluted to 100 M in PBS. Starting with these monomeric peptide preparations, A␤-488 or -633 and non-labeled A␤ 1-42 were further incubated at 4 • C for 24 h to promote oligomeric formation, and at 37 • C for 24 h to promote fibril formation [16].…”

Section: Preparation Of Aβ 1-42mentioning

confidence: 99%

“…We previously measured in vivo changes of the redox status (the balance between antioxidants and oxidants) in the brain of AD model mice noninvasively by three-dimensional (3D) electron paramagnetic resonance (EPR) imaging, and demonstrated a significantly accelerated change in redox state in model mice showing increased A␤ deposition and glial activation [14]. We reported that proinflammatory cytokines such as TNF␣ increased in the microglial fraction of A␤-stimulated AD mice brain [15], and that microglia internalized A␤ through the TLR4/CD14 complex as one of A␤ clearance pathways [16]. From these findings, we focused on microglial function in AD progression, and whether modification of microglial function prevents progression of AD through suppression of oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Yokokawa

Iwahara

Hisahara

et al. 2019

JAD

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Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer's disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-␤ (A␤) pathology and microglial function. MSC transplantation reduced A␤ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around A␤ deposits and prompted microglial A␤ uptake and clearance as shown by higher frequency of A␤-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in A␤ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced A␤ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving A␤ pathology in AD model mice.

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Section: Discussionmentioning

confidence: 99%

“…We previously reported that microglial CD14 was an important receptor for A␤ uptake [16]. Therefore, we examined microglial CD14 expression in APdE9-MSC mice.…”

Section: Msc Transplantation Upregulated Microglial Cd14 Expressionmentioning

confidence: 95%

Section: Preparation Of Aβ 1-42mentioning

confidence: 99%

Section: Preparation Of Aβ 1-42mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Yokokawa

Iwahara

Hisahara

et al. 2019

JAD

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Triggering receptor expressed on myeloid cells 2 activation downregulates toll‐like receptor 4 expression and ameliorates cognitive impairment in the Aβ_1‐42‐induced Alzheimer's disease mouse model

Qin

Zhou

et al. 2020

Synapse

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Increasing evidence suggests that changes in the triggering receptor expressed on myeloid cells 2 (TREM2) is closely correlated with the pathological development of Alzheimer's disease (AD). However, the biological function and related role of this change remain poorly understood. Higher TREM2 expression has been reported in the brain of AD patients than in normal controls. Here, levels of TREM2 gene and protein levels were observed to be higher in both cortex and hippocampus of the Aβ1‐42‐induced AD mice than in those of the wild type mice. Together with in vitro experimental data, we found that the anti‐inflammatory role of TREM2 was, to some extent, limited and potentially counteracted by the hyperactive toll‐like receptor 4 (TLR4) in the AD mice. In this context, Interleukin 4 (IL‐4), as an agonist of TREM2, was administered to the AD mice to persistently activate TREM2. Interestingly, TREM2 activation in IL‐4‐treated AD mice led to an elevation in lysosomes and microtubule‐associated protein 1 light chain 3 (LC3) II/I expression, demonstrating that the level of microglia autophagy was increased. Increased autophagy significantly downregulated the expression levels of caspase recruitment domain‐containing protein 9 (CARD9) and TLR4, potentially weakening the CARD9‐TLR4 pathway and suppressing the TLR4‐mediated pro‐inflammatory effect in IL‐4‐treated AD mice. Furthermore, data acquired from Morris water maze testing indicated that IL‐4 administration could ameliorate cognitive impairment in the AD mice. In conclusion, the findings from in vitro and in vivo experiments suggest that TREM2 might represent a potential drug target to treat neuroinflammation in AD.

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CD14: Not Just Chaperone, But a Key-Player in Inflammation

Gioia

Zanoni

2020

The Role of Toll-Like Receptor 4 in Infectious and Non Infectious Inflammation

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The cluster of differentiation 14 (CD14) is a receptor that helps the detection of microbial products, acting as an accessory molecule for several Toll-like receptors (TLRs). Recently, this view was challenged by the discovery that CD14 not only regulates TLR-ligand interactions but also autonomously controls inflammatory responses. Moreover, CD14 is also implicated in the recognition of hostderived tissue stress signals, such as non-enzymatically modified lipids and protein aggregates, playing homeostatic roles as well as initiating detrimental responses associated to chronic inflammation. Here we will discuss the ability of CD14 to bind different exogenous and endogenous ligands and how CD14 coordinates inflammatory responses.

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CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway

Cited by 21 publications

References 47 publications

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Triggering receptor expressed on myeloid cells 2 activation downregulates toll‐like receptor 4 expression and ameliorates cognitive impairment in the Aβ_1‐42‐induced Alzheimer's disease mouse model

CD14: Not Just Chaperone, But a Key-Player in Inflammation

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CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway

Cited by 21 publications

References 47 publications

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress

Triggering receptor expressed on myeloid cells 2 activation downregulates toll‐like receptor 4 expression and ameliorates cognitive impairment in the Aβ1‐42‐induced Alzheimer's disease mouse model

CD14: Not Just Chaperone, But a Key-Player in Inflammation

Contact Info

Product

Resources

About

Triggering receptor expressed on myeloid cells 2 activation downregulates toll‐like receptor 4 expression and ameliorates cognitive impairment in the Aβ_1‐42‐induced Alzheimer's disease mouse model