Macrophagic HDAC3 inhibition ameliorates Dextran Sulfate Sodium induced inflammatory bowel disease through GBP5-NLRP3 pathway.

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease, characterized by dysregulated immune response. HDAC3 is reported to be an epigenetic brake in inflammation, playing critical roles in macrophages. However, its role in IBD is unclear. In our study, we found HDAC3 was upregulated in CX3CR1-positive cells in the mucosa from IBD mice. Conditional knockout (cKO) of Hdac3 in CX3CR1 positive cells attenuated the disease severity of Dextran Sulfate Sodium (DSS)-induced colitis. In addition, inhibition of HDAC3 with RGFP966 could also alleviate the DSS-induced tissue injury and inflammation in IBD. The RNA sequencing results revealed that Hdac3 cKO restrained DSS-induced upregulation of genes in the pathways of cytokine-cytokine receptor interaction, complement and coagulation cascades, chemokine signaling, and extracellular matrix receptor interaction. We also identified that Guanylate-Binding Protein 5 (GBP5) was transcriptionally regulated by HDAC3 in monocytes by RNA sequencing. Inhibition of HDAC3 resulted in decreased transcriptional activity of interferon-gamma-induced expression of GBP5 in CX3CR1-positive cells, such as macrophages and microglia. Overexpression of HDAC3 upregulated the transcriptional activity of GBP5 reporter. Lastly, conditional knockout of Hdac3 in macrophages (Hdac3 mKO) attenuated the disease severity of DSS-induced colitis. In conclusion, inhibition of HDAC3 in macrophages could ameliorate the disease severity and inflammatory response in colitis by regulating GBP5-NLRP3 axis, identifying a new therapeutic avenue for the treatment of colitis.

GABAergic Neurons in the Dorsal-Intermediate Lateral Septum Regulate Sleep-Wakefulness and Anesthesia in Mice.

BACKGROUND: The γ-aminobutyric acid-mediated (GABAergic) inhibitory system in the brain is critical for regulation of sleep-wake and general anesthesia. The lateral septum contains mainly GABAergic neurons, being cytoarchitectonically divided into the dorsal, intermediate, and ventral parts. This study hypothesized that GABAergic neurons of the lateral septum participate in the control of wakefulness and promote recovery from anesthesia. METHODS: By employing fiber photometry, chemogenetic and optogenetic neuronal manipulations, anterograde tracing, in vivo electrophysiology, and electroencephalogram/electromyography recordings in adult male mice, the authors measured the role of lateral septum GABAergic neurons to the control of sleep-wake transition and anesthesia emergence and the corresponding neuron circuits in arousal and emergence control. RESULTS: The GABAergic neurons of the lateral septum exhibited high activities during the awake state by in vivo fiber photometry recordings (awake vs. non-rapid eye movement sleep: 3.3 ± 1.4% vs. -1.3 ± 1.2%, P < 0.001, n = 7 mice/group; awake vs. anesthesia: 2.6 ± 1.2% vs. -1.3 ± 0.8%, P < 0.001, n = 7 mice/group). Using chemogenetic stimulation of lateral septum GABAergic neurons resulted in a 100.5% increase in wakefulness and a 51.2% reduction in non-rapid eye movement sleep. Optogenetic activation of these GABAergic neurons promoted wakefulness from sleep (median [25th, 75th percentiles]: 153.0 [115.9, 179.7] s to 4.0 [3.4, 4.6] s, P = 0.009, n = 5 mice/group) and accelerated emergence from isoflurane anesthesia (514.4 ± 122.2 s vs. 226.5 ± 53.3 s, P < 0.001, n = 8 mice/group). Furthermore, the authors demonstrated that the lateral septum GABAergic neurons send 70.7% (228 of 323 cells) of monosynaptic projections to the ventral tegmental area GABAergic neurons, preferentially inhibiting their activities and thus regulating wakefulness and isoflurane anesthesia depth. CONCLUSIONS: The results uncover a fundamental role of the lateral septum GABAergic neurons and their circuit in maintaining awake state and promoting general anesthesia emergence time.

1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis.

NOD-like receptor (NLR) family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in inflammation-associated diseases such as multiple sclerosis, Parkinson's disease, and stroke. Targeting the NLRP3 inflammasome is beneficial to these diseases, but few NLRP3 inflammasome-selective inhibitors are identified to date. Essential oils (EOs) are liquid mixtures of volatile and low molecular-weight organic compounds extracted from aromatic plants, which show various pharmacological activities, including antibacterial, antifungal, antiviral, antioxidant, and anti-inflammatory properties. In this study we screened active ingredients from essential oils, and identified 1,2,4-trimethoxybenzene (1,2,4-TTB) as a selective NLRP3 inflammasome inhibitor. We showed that 1,2,4-TTB (1 mM) markedly suppressed nigericin- or ATP-induced NLRP3 inflammasome activation, thus decreased caspase-1 activation and IL-1ß secretion in immortalized murine bone marrow-derived macrophages (iBMDMs) and in primary mouse microglia. Moreover, 1,2,4-TTB specifically inhibited the activation of NLRP3 inflammasome without affecting absent in melanoma 2 (AIM2) inflammasome activation. We further demonstrated that 1,2,4-TTB inhibited oligomerization of the apoptosis-associated speck-like protein containing a CARD (ASC) and protein-protein interaction between NLRP3 and ASC, thus blocking NLRP3 inflammasome assembly in iBMDMs and in primary mouse macrophages. In mice with experimental autoimmune encephalomyelitis (EAE), administration of 1,2,4-TTB (200 mg · kg-1 · d-1, i.g. for 17 days) significantly ameliorated EAE progression and demyelination. In conclusion, our results demonstrate that 1,2,4-TTB is an NLRP3 inflammasome inhibitor and attenuates the clinical symptom and inflammation of EAE, suggesting that 1,2,4-TTB is a potential candidate compound for treating NLRP3 inflammasome-driven diseases, such as multiple sclerosis.

The function of NOD-like receptors in central nervous system diseases.

NOD-like receptors (NLRs) are critical cytoplasmic pattern-recognition receptors (PRRs) that play an important role in the host innate immune response and immunity homeostasis. There is a growing body of evidence that NLRs are involved in a wide range of inflammatory diseases, including cancer, metabolic diseases, and autoimmune disorders. Recent studies have indicated that the proteins of the NLR family are linked with the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), and psychological diseases. In this review, we mainly focus on the role of NLRs and the underlying signaling pathways in central nervous system (CNS) diseases. © 2016 Wiley Periodicals, Inc.

Mrgprb2-mediated mast cell activation exacerbates Modic changes by regulating immune niches.

Modic changes are radiographic features associated with microfracture, low-virulence organism infection and chronic inflammation with inflammatory cell infiltration in the vertebral endplate region. Mast cells, as innate immune cells similar to macrophages, are present in painful degenerated intervertebral discs. However, the involvement and mechanisms of mast cells in the development of Modic changes remain unclear. Herein, we found increased mast cell infiltration in samples from patients with Modic changes and in mouse models of Modic changes. To clarify the role of mast cells in the progression of Modic changes, we used mast cell-deficient (KITW-SH/W-SH) mice to construct a model of Modic changes and found that the severity of Modic changes in KITW-SH/W-SH mice was significantly lower than that in WT mice. These findings were further supported by the use of a mast cell-specific activator (compound 48/80) and a stabilizer (cromolyn). Furthermore, we found that mast cells were not activated via the classic IgE pathway in the Modic change models and that Mrgprb2 is the specific receptor for mast cell activation reported in recent studies. Then, we utilized Mrgprb2 knockout mice to demonstrate that Mrgprb2 knockout inhibited mast cell activation and thus reduced the degree of Modic changes. Transcriptomic sequencing revealed aberrant PI3K-AKT and MAPK pathway activation in the Mrgprb2-deficient mast cells. Additionally, Mrgpbrb2-activated mast cells regulate immune niches by recruiting macrophages, promoting M1 polarization and reducing M2 polarization, thereby promoting the progression of Modic changes. These findings suggest that mast cells may serve as a novel therapeutic target for addressing Modic changes.

PRRC2B modulates oligodendrocyte progenitor cell development and myelination by stabilizing Sox2 mRNA.

Oligodendrocyte progenitor cells (OPCs) differentiate into myelin-producing cells and modulate neuronal activity. Defects in OPC development are associated with neurological diseases. N6-methyladenosine (m6A) contributes to neural development; however, the mechanism by which m6A regulates OPC development remains unclear. Here, we demonstrate that PRRC2B is an m6A reader that regulates OPC development and myelination. Nestin-Cre-mediated Prrc2b deletion affects neural stem cell self-renewal and glial differentiation. Moreover, the oligodendroglia lineage-specific deletion of Prrc2b reduces the numbers of OPCs and oligodendrocytes, causing hypomyelination and impaired motor coordination. Integrative methylated RNA immunoprecipitation sequencing, RNA sequencing, and RNA immunoprecipitation sequencing analyses identify Sox2 as the target of PRRC2B. Notably, PRRC2B, displaying separate and cooperative functions with PRRC2A, stabilizes mRNA by binding to m6A motifs in the coding sequence and 3' UTR of Sox2. In summary, we identify the posttranscriptional regulation of PRRC2B in OPC development, extending the understanding of PRRC2 family proteins and providing a therapeutic target for myelin-related disorders.

FATP2 regulates Osteoclastogenesis by increasing lipid metabolism and ROS production.

Lipid metabolism plays a crucial role in maintaining bone homeostasis, particularly in osteoclasts (OCs) formation. Here, we found the expression level of FATP2, a transporter for long-chain and very-long-chain fatty acids, was significantly upregulated during OC differentiation and in the bone marrow of mice fed a high-fat diet (HFD). Notably, the use of FATP2 siRNA or a specific inhibitor (Lipofermata) resulted in significant inhibition of OC differentiation while only slightly affecting osteoblasts (OBs). In pathological models of bone loss induced by LPS or OVX, in vivo treatment with Lipofermata was able to rescue the loss of bone mass by inhibiting OC differentiation. RNA sequencing (RNA-seq) revealed that Lipofermata reduced fatty acid ß-oxidation and inhibited energy metabolism, while regulating reactive oxygen species (ROS) metabolism to decrease ROS production, ultimately inhibiting OC differentiation. Treatment with Lipofermata, either in vivo or in vitro, effectively rescued the overactivation of OCs, indicating that FATP2 regulated OC differentiation by modulating fatty acid uptake and energy metabolism. These findings suggested that targeting FATP2 may represent a promising therapeutic approach for pathological osteoporosis.

The inhibition of osteoclastogenesis by Lipofermata, a FATP2 inhibitor, was achieved through the reprogramming of energy metabolism and regulation of ROS levels. In both pathological bone loss and HFD-induced osteoporosis models, the expression levels of FATP2 were significantly upregulated and Lipofermata demonstrated potential therapeutic effects in the pathological bone loss model.

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919).

Introduction: Major depression disorder (MDD) is a common and potentially life-threatening mental illness; however, data on its pathogenesis and effective therapeutic measures are lacking. Pathological changes in astrocytes play a pivotal role in MDD. While hypidone hydrochloride (YL-0919), an independently developed antidepressant, has shown rapid action with low side effects, its underlying astrocyte-specific mechanisms remain unclear. Methods: In our study, mice were exposed to chronic restraint stress (CRS) for 14 days or concomitantly administered YL-0919/fluoxetine. Behavioral tests were applied to evaluate the depression model; immunofluorescence and immunohistochemistry staining were used to explore morphological changes in astrocytes; astrocyte-specific RNA sequencing (RNA-Seq) analysis was performed to capture transcriptome wide alterations; and ATP and oxygen consumption rate (OCR) levels of primary astrocytes were measured, followed by YL-0919 incubation to appraise the alteration of energy metabolism and mitochondrial oxidative phosphorylation (OXPHOS). Results: YL-0919 alleviated CRS-induced depressive-like behaviors faster than fluoxetine and attenuated the number and morphologic deficits in the astrocytes of depressed mice. The changes of gene expression profile in astrocytes after CRS were partially reversed by YL-0919. Moreover, YL-0919 improved astrocyte energy metabolism and mitochondrial OXPHOS in astrocytes. Conclusion: Our results provide evidence that YL-0919 exerted a faster-onset antidepressant effect on CRS-mice possibly via astrocyte structural remodeling and mitochondria functional restoration.

The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling.

The ubiquitin‒proteasome system (UPS) plays a key role in maintaining protein homeostasis and bone remodelling. However, the role of deubiquitinating enzymes (DUBs) in bone resorption is still not well defined. Here, we identified the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) as a negative regulator of osteoclastogenesis by using the GEO database, proteomic analysis, and RNAi. Osteoclast-specific UCHL1 conditional knockout mice exhibited a severe osteoporosis phenotype in an ovariectomized model. Mechanistically, UCHL1 deubiquitinated and stabilized the transcriptional coactivator with PDZ-binding motif (TAZ) at the K46 residue, thereby inhibiting osteoclastogenesis. The TAZ protein underwent K48-linked polyubiquitination, which was degraded by UCHL1. As a substrate of UCHL1, TAZ regulates NFATC1 through a nontranscriptional coactivator function by competing with calcineurin A (CNA) for binding to NFATC1, which inhibits NFATC1 dephosphorylation and nuclear transport to impede osteoclastogenesis. Moreover, overexpression of UCHL1 locally alleviated acute and chronic bone loss. These findings suggest that activating UCHL1 may serve as a novel therapeutic approach targeting bone loss in various bone pathological states.

A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche.

Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4+ lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the VSIg4+ lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.

Association Between Burst-Suppression Latency and Burst-Suppression Ratio Under Isoflurane or Adjuvant Drugs With Isoflurane Anesthesia in Mice.

The same doses of anesthesia may yield varying depths of anesthesia in different patients. Clinical studies have revealed a possible causal relationship between deep anesthesia and negative short- and long-term patient outcomes. However, a reliable index and method of the clinical monitoring of deep anesthesia and detecting latency remain lacking. As burst-suppression is a characteristic phenomenon of deep anesthesia, the present study investigated the relationship between burst-suppression latency (BSL) and the subsequent burst-suppression ratio (BSR) to find an improved detection for the onset of intraoperative deep anesthesia. The mice were divided young, adult and old group treated with 1.0% or 1.5% isoflurane anesthesia alone for 2 h. In addition, the adult mice were pretreated with intraperitoneal injection of ketamine, dexmedetomidine, midazolam or propofol before they were anesthetized by 1.0% isoflurane for 2 h. Continuous frontal, parietal and occipital electroencephalogram (EEG) were acquired during anesthesia. The time from the onset of anesthesia to the first occurrence of burst-suppression was defined as BSL, while BSR was calculated as percentage of burst-suppression time that was spent in suppression periods. Under 1.0% isoflurane anesthesia, we found a negative correlation between BSL and BSR for EEG recordings obtained from the parietal lobes of young mice, from the parietal and occipital lobes of adult mice, and the occipital lobes of old mice. Under 1.5% isoflurane anesthesia, only the BSL calculated from EEG data obtained from the occipital lobe was negatively correlated with BSR in all mice. Furthermore, in adult mice receiving 1.0% isoflurane anesthesia, the co-administration of ketamine and midazolam, but not dexmedetomidine and propofol, significantly decreased BSL and increased BSR. Together, these data suggest that BSL can detect burst-suppression and predict the subsequent BSR under isoflurane anesthesia used alone or in combination with anesthetics or adjuvant drugs. Furthermore, the consistent negative correlation between BSL and BSR calculated from occipital EEG recordings recommends it as the optimal position for monitoring burst-suppression.

Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Neuronal calcium dysfunction and microglial-mediated neuroinflammation are closely associated with the development of AD. However, it remains unknown whether calcium dysfunction contributes to microglial activation and, in turn, AD pathology in vivo. In this study, we demonstrated that the expression of calcium homeostasis modulator family protein 2 (Calhm2) is increased in an AD mouse model. In 5×FAD mice carrying five familial AD gene mutations, both conventional knockout of Calhm2 and conditional microglial knockout of Calhm2 significantly reduced amyloid ß deposition, neuroinflammation, and cognitive impairments. Mechanistically, knockout of Calhm2 inhibited microglial proinflammatory activity but increased phagocytic activity, leading to restoration of the balance between inflammation and phagocytosis. In addition, knockout of Calhm2 reduced acute LPS-induced neuroinflammation. These results highlight an important role for Calhm2 in microglial activation and provide a potential therapeutic target for diseases related to microglia-mediated neuroinflammation.

Hematopoietic Cell Kinase (HCK) Is Essential for NLRP3 Inflammasome Activation and Lipopolysaccharide-Induced Inflammatory Response In Vivo.

Activation of the NLRP3 inflammasome results in caspase 1 cleavage, which subsequently leads to IL-1ß and IL-18 secretion, as well as pyroptosis, and aberrant activation of the inflammasome is involved in several diseases such as type 2 diabetes, atherosclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. NLRP3 activity is regulated by various kinases. Genetic and pharmacological inhibition of the hematopoietic cell kinase (HCK), a member of the Src family of non-receptor tyrosine kinases (NRTKs) primarily expressed in myeloid cells, has previously been shown to ameliorate inflammation, indicating that it may be involved in the regulation of microglia function. However, the underlying mechanism is not known. Hence, in this study, we aimed to investigate the role of HCK in NLRP3 inflammasome activation. We demonstrated that HCK silencing inhibited NLRP3 inflammasome activation. Furthermore, the HCK-specific inhibitor, A419259, attenuated the release of IL-1ß and caspase 1(P20) from the macrophages and microglia and reduced the formation of the apoptosis-associated speck-like protein with a CARD domain (ASC) oligomer. We also observed that HCK binds to full length NLRP3 and its NBD(NACHT) and LRR domains, but not to the PYD domain. In vivo, the HCK inhibitor attenuated the LPS-induced inflammatory response in the liver of LPS-challenged mice. Collectively, these results suggested that HCK plays a critical role in NLRP3 inflammasome activation. Our results will enhance current understanding regarding the effectiveness of HCK inhibitors for treating acute inflammatory diseases.

HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway.

Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study aimed to investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury, and to identify possible strategies for the treatment of ischemic stroke. Methods: To demonstrate that microglial histone deacetylase 3 (HDAC3) regulates the microglial cGAS-stimulator of interferon genes (cGAS-STING) pathway and is involved in I/R-induced neuroinflammation and brain injury, a series of cell biological, molecular, and biochemical approaches were utilized. These approaches include transient middle cerebral artery occlusion (tMCAO), real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, chromosome-immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), dual-luciferase reporter assay, immunohistochemistry, and confocal imaging. Results: The microglial cGAS- STING pathway was activated by mitochondrial DNA, which promoted the formation of a pro-inflammatory microenvironment. In addition, we revealed that HDAC3 transcriptionally promoted the expression of cGAS and potentiated the activation of the cGAS-STING pathway by regulating the acetylation and nuclear localization of p65 in microglia. Our in vivo results indicated that deletion of cGAS or HDAC3 in microglia attenuated I/R-induced neuroinflammation and brain injury. Conclusion: Collectively, we elucidated that the HDAC3-p65-cGAS-STING pathway is involved in the development of I/R-induced neuroinflammation, identifying a new therapeutic avenue for the treatment of ischemic stroke.

Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice.

Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)-cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1ß in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. Abbreviations: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.

Sodium rutin ameliorates Alzheimer's disease-like pathology by enhancing microglial amyloid-ß clearance.

The accumulation of aggregated amyloid-ß (Aß) in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD), which also includes synaptic impairment, neuroinflammation, neuronal loss, and eventual cognitive defects. Emerging evidence suggests that impairment of Aß phagocytosis and clearance is a common phenotype in late-onset AD. Rutin (quercetin-3-rutinoside) has long been investigated as a natural flavonoid with different biological functions in some pathological circumstances. Sodium rutin (NaR), could promote Aß clearance by increasing microglial by increasing the expression levels of phagocytosis-related receptors in microglia. Moreover, NaR promotes a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS (oxidative phosphorylation), which could provide microglia with sufficient energy (ATP) for Aß clearance. Thus, NaR administration could attenuate neuroinflammation and enhance mitochondrial OXPHOS and microglia-mediated Aß clearance, ameliorating synaptic plasticity impairment and eventually reversing spatial learning and memory deficits. Our findings suggest that NaR is a potential therapeutic agent for AD.