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Background Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism may associate with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. Methods A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and spike protein and between ApoE and also the SARS-CoV-2 primary receptor ACE2. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. Results ApoE gene polymorphism (ε4 carries genotypes VS non-ε4 carries genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI: 1.18–1.76) and progression (P in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1–7. Conclusions ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin–angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.

GRK5 is a member of the G protein-coupled receptors (GPCRs) kinase family and is closely associated with Alzheimer's disease (AD). However, the biological function of GRK5 in the brain and the causal link between GRK5 deficiency and AD-like pathology is unknown. Here, we show that GRK5 is reduced in the AD mouse brain, and mice with reduced GRK5 in the hippocampus induce cognitive impairment. AD-like molecular pathology, such as significant neuronal damage and loss, enhanced tau proteins phosphorylation, and increased level of Aβ peptides in the hippocampus were also observed in the GRK5 deficiency mice. Mechanismly, GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. CRK5 deficiency elicits microglial morphology change and pfo-inflammation-associated gene increase. In addition, transcriptional analysis of hippocampal tissues revealed that neuroactive ligand-receptor interactions and TNF signaling are striking changes in GRK5 deficiency mice, which have the same trend in the AD mouse. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. Provide a possible mechanism that GRK5 maintains the microglia homeostasis, and its loss may induce microglia function deficit and cause other AD-related molecular pathogenesis.

GRK5 is a member of the G protein-coupled receptor (GPCR) kinase family and is closely associated with heart and nervous system disease. It has been reported that GRK5 is closely related to cerebral nerve function and neurodegenerative diseases. However, the biological function of GRK5 in the brain and the influence of GRK5 deficiency on cognitive dysfunction associated with neurodegenerative diseases are unknown. Here, we reported that mice with reduced GRK5 in the hippocampus exhibit cognitive impairment and some Alzheimer's disease (AD)-related molecular pathologies, such as significant neuronal damage and loss, enhanced tau protein phosphorylation, and increased levels of Aβ peptides in the hippocampus. Mechanistically, we observed that GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. GRK5 deficiency elicits microglial morphology changes and proinflammatory-associated gene increases. In addition, transcriptional analysis of hippocampal tissues revealed striking changes in neuroactive ligand‒receptor interactions and TNF signaling in GRK5-deficient mice. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. This finding suggests a possible mechanism by which GRK5 maintains microglial homeostasis, and its loss may induce microglial function deficits and cause some AD-related molecular pathogenesis.

The tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and currently has no effective treatment. Mainstream research on the mechanisms and therapeutic targets of AD is focused on the two most important hallmarks, Aβ and Tau, but the results from clinical studies are not encouraging. Abnormal microglial polarization is a clear typical pathological feature in the progression of AD. Microglia can be neuroprotective by degrading and removing Aβ and Tau. However, under AD conditions, microglia transform into a pro-inflammatory phenotype that decreases the phagocytic activity of microglia, damages neurons and promotes the pathology of AD. We previously reported that a miR-146a polymorphism is associated with sporadic AD risk, and the nasal administration of miR-146a mimics reduced cognitive impairment and the main pathological features of AD. However, it is not clear by what mechanism miR-146a resists the pathological process of AD. In this study, we discovered that microglia-specific miR-146a overexpression reduced cognitive deficits in learning and memory, attenuated neuroinflammation, reduced Aβ levels, ameliorated plaque-associated neuritic pathology, and prevented neuronal loss in APP/PS1 transgenic mice. In addition, we found that miR-146a switched the microglial phenotype, reduced pro-inflammatory cytokines and enhanced phagocytic function to protect neurons in vitro and in vivo. Moreover, transcriptional analysis confirmed that miR-146a opposed the pathological process of AD mainly through neuroinflammation-related pathways. In summary, our results provide sufficient evidence for the mechanism by which miR-146a opposes AD and strengthen the conclusion that miR-146a is a promising target for AD and other microglia-related diseases.

Alzheimer’s disease (AD) is the most common cause of dementia and cannot be cured. The etiology and pathogenesis of AD is still not fully understood, the genetics is considered to be one of the most important factors for AD onset, and the identified susceptible genes could provide clues to the AD mechanism and also be the potential targets. MicroRNA-146a-5p (miR-146a) is well known in the regulation of the inflammatory response, and the functional SNP of miR-146a was associated with AD risk. In this study, using a noninvasive nasal administration, we discovered that a miR-146a agomir (M146AG) rescued cognitive impairment in the APP/PS1 transgenic mouse and alleviated the overall pathological process in the AD mouse model, including neuroinflammation, glia activation, Aβ deposit, and tau phosphorylation in hippocampi. Furthermore, the transcriptional analysis revealed that besides the effect of neuroinflammation, M146AG may serve as a multi-potency target for intervention in AD. In addition, Srsf6 was identified as a target of miR-146a, which may play a role in AD progression. In conclusion, our study supports that the nasal-to-brain pathway is efficient and operable for the brain administration of microRNAs (miRNAs), and that miR-146a may be a new potential target for AD treatment. Keywords: miR-146a-5p, Alzheimer’s disease, intranasal administration, srsf6, neuroinflammation

Background: The ε4 allele of the Apolipoprotein E (APOE) gene is a major genetic risk determinant of sporadic Alzheimer's disease (AD). Its protein product APOE4 has been demonstrated to coffers deleterious effects for various neurodegenerative disorders related to cognitive impairment, including AD. A line of evidence implied that APOE4 affects these diseases partly through its synaptic damage. However, the mechanisms underlying this have not been fully interpreted.Methods: Proteomics analysis, Co-immunoprecipitation assay (Co-IP), Bimolecular fluorescence complementation (BIFC), and Proximity ligation assay (PLA) assays were used to screen and verify the interactome of APOE, which in an APOE4-priority manner. The molecular docking and molecular dynamic analysis were conducted to elucidate the molecular mechanisms that APOE3 differs from APOE4 in the binding ability of VAMP2. Adeno-associated virus expressing APOE3 and APOE4 was stereotaxically injected into the Hippocampus of Apoe-/- mice, and in vitro recombinant proteins experiments were conducted to verify the AOPE on soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assemble. FM4-64 fluorescent dye labeling assay was explored in hippocampus from APOE3-TR and APOE4-TR mice to study the APOE genotype effect on synaptic vesicle release.Results:Using proteomics analysis, we screened interactomes of APOE3 and APOE4 in neurons, respectively. Then, VAMP2 protein was selected for further analysis through related bioinformatics analysis. Via Co-IP, BIFC, and PLA assays,we demonstrated that APOE directly interacts with VAMP2 in an E4 > E3 manner in vitro and in vivo. The molecular docking and molecular dynamic analysis suggested that the APOE4-VAMP2 complex was more stable and had higher affinity than APOE3-VAMP2, may due to the increased contribution of hydrogen bonding, hamper VAMP2 to form the SNARE complex. The further in vitro and in vivo results suggest that APOE4 blocks the SNARE complex assembly, negatively regulating synaptic vesicle release, finally contributing to the synaptic damage and cognitive impairment.Conclusions:Our findings identify SNARE protein as an APOE interactor, and APOE4 isoform effects on SNARE complex formation, mediates APOE4-induced synaptic dysfunction. Our results provide insights into APOE4-mediated synapse toxicity, and suggested new avenues for specifically targeting early presynaptic dysfunction in AD.

Background/Aims: Increasing evidence suggests the important role of sirtuin 2 (SIRT2) in the pathology of Parkinson’s disease (PD). However, the association between potential functional polymorphisms in the SIRT2 gene and PD still needs to be identified. Exploring the molecular mechanism underlying this potential association could also provide novel insights into the pathogenesis of this disorder. Methods: Bioinformatics analysis and screening were first performed to find potential microRNAs (miRNAs) that could target the SIRT2 gene, and molecular biology experiments were carried out to further identify the regulation between miRNA and SIRT2 and characterize the pivotal role of miRNA in PD models. Moreover, a clinical case-control study was performed with 304 PD patients and 312 healthy controls from the Chinese Han population to identify the possible association of single nucleotide polymorphisms (SNPs) within the miRNA binding sites of SIRT2 with the risk of PD. Results: Here, we demonstrate that miR-486-3p binds to the 3’ UTR of SIRT2 and influences the translation of SIRT2. MiR-486-3p mimics can decrease the level of SIRT2 and reduce a-synuclein (α-syn)-induced aggregation and toxicity, which may contribute to the progression of PD. Interestingly, we find that a SNP, rs2241703, may disrupt miR-486-3p binding sites in the 3’ UTR of SIRT2, subsequently influencing the translation of SIRT2. Through the clinical case-control study, we further verify that rs2241703 is associated with PD risk in the Chinese Han population. Conclusion: The present study confirms that the rs2241703 polymorphism in the SIRT2 gene is associated with PD in the Chinese Han population, provides the potential mechanism of the susceptibility locus in determining PD risk and reveals a potential target of miRNA for the treatment and prevention of PD.

Radiation-induced brain injury (RBI) is a serious complication in patients who have received radiotherapy for head and neck tumors. Currently, there is a scarcity of information on early diagnostic and preventive methods of RBI. Accumulating evidence suggests that microRNAs are involved in the regulation of radiation injury, but the molecular biological mechanism of miRNAs in RBI is largely unknown. Therefore, in our study, microRNA sequencing was used to discover differential miRNAs in the hippocampus of RBI-modeled mice, which suggested that miR-741-3p was most significantly upregulated. To clarify the underlying mechanism of miR-741-3p in RBI-modeled mice, an inhibitor of miR-741-3p (antagomiR-741) was delivered into the brain via the nasal passage before irradiation. The delivery of antagomiR-741 significantly reduced miR-741-3p levels in the hippocampus of RBI-modeled mice, and the cognitive dysfunction and neuronal apoptosis induced by radiation were also alleviated at 6 weeks postirradiation. Downregulation of miR-741-3p was found to improve the protrusion and branching status of microglia after irradiation and reduced the number of GFAP-positive astrocytes. Additionally, antagomiR-741 suppressed the radiation-induced production of pro-inflammatory cytokines IL-6 and TNF-α in the hippocampus and S100B in the serum. Furthermore, Ddr2, PKCα and St8sia1 were revealed as target genes of miR-741-3p and as potential regulatory targets for RBI. Overall, our study provides identification and functional evaluation of miRNA in RBI and lays the foundation for improving the prevention strategy for RBI based on the delivery of miRNA via the nose-brain pathway.

Sirtuin 2 (SIRT2) is an NAD+ dependent deacetylase that is the most abundant sirtuin protein in the brain. Accumulating evidence revealed the role of SIRT2 in a wide range of biological processes and age‐related diseases. However, the pivotal mechanism of SIRT2 played in Alzheimer's disease (AD) remains unknown. Here, we report that pharmacological inactivation of SIRT2 has a beneficial effect in AD. The deacetylase inhibitor of SIRT2 rescued the cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mouse (APP/PS1 mouse), and the BACE1 cleavage was weakened to reduce the β‐amyloid (Aβ) production in the hippocampus. Moreover, we firstly identified that Reticulon 4B (RTN4B) played a crucial role between SIRT2/BACE1 regulation in AD. RTN4B, as a deacetylation substrate for SIRT2, the deacetylation by SIRT2 drived the ubiquitination and degradation of RTN4B and then the disturbed RTN4B interacted with and influenced the expression of BACE1. When we overexpressed RTN4B in neurons of the hippocampus in the AD mouse model, the abnormal Aβ accumulation and cognitive impairment were ameliorated, consistent with the results of SIRT2 inhibition in vivo. Moreover, we showed that the regulatory effect of SIRT2 on BACE1 is dependent on RTN4B. When RTN4B was knocked down, the effects of SIRT2 inhibition on the BACE1 level, Aβ pathology, and AD‐liked behaviors were also blocked. Collectively, we provide evidence that SIRT2 may be a potential target for AD; the new found SIRT2/RTN4B/BACE1 pathological pathway is one of the critical mechanisms for the improvement of SIRT2 on AD., The repression of SIRT2 deacetylase activity could ameliorate Aβ pathology and cognitive deficits in the Alzheimer's Disease (AD) mouse model. As for the mechanism, SIRT2 influences the β‐secretase 1 (BACE1) by directly deacetylates reticulon 4B protein (RTN4B), thus affect the production of Aβ, finally contribute to the AD progress. These data marked that SIRT2/RTN4B/BACE1 is a new critical pathological pathway in recusing AD.

Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases., Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. In vitro results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the ADAM10 gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention in vivo decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model.

Sirtuin 2 (SIRT2) is an NAD+-dependent deacetylase that was under studied compared to other sirtuin family members. SIRT2 is the only sirtuin protein which is predominantly found in the cytoplasm but is also found in the mitochondria and in the nucleus. Recently, accumulating evidence has uncovered a growing number of substrates and additional detailed functions of SIRT2 in a wide range of biological processes, marking its crucial role. Here, we give a comprehensive profile of the crucial physiological functions of SIRT2 and its role in neurological diseases, cancers, and other diseases. This review summarizes the functions of SIRT2 in the nervous system, mitosis regulation, genome integrity, cell differentiation, cell homeostasis, aging, infection, inflammation, oxidative stress, and autophagy. SIRT2 inhibition rescues neurodegenerative disease symptoms and hence SIRT2 is a potential therapeutic target for neurodegenerative disease. SIRT2 is undoubtedly dysfunctional in cancers and plays a dual-faced role in different types of cancers, and although its mechanism is unresolved, SIRT2 remains a promising therapeutic target for certain cancers. In future, the continued rapid growth in SIRT2 research will help clarify its role in human health and disease, and promote the progress of this target in clinical practice.

G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase whose dysfunction results in cognitive impairment and Alzheimer-like pathology, including tau hyperphosphorylation. However, the mechanisms whereby GRK5 influences tau phosphorylation remain incompletely understood. In the current study, we showed that GRK5 influenced the phosphorylation of tau via glycogen synthase kinase 3β (GSK3β). The activity of both tau and GSK3β in the hippocampus was increased in aged GRK5-knockout mice, which is consistent with what occurs in APP/PS1 transgenic mice. Furthermore, GRK5 regulated the activity of GSK3β and phosphorylated tau in vitro. Regardless of changes of GRK5 protein levels, tau hyperphosphorylation remained reduced after GSK3β activity was inhibited, suggesting that GRK5 may specifically influence tau hyperphosphorylation by modulating GSK3β activity. Taken together, our findings suggest that GRK5 deficiency contributes to the pathogenesis of Alzheimer's disease by influencing the hyperphosphorylation of tau through the activation of GSK3β.