RESUMEN
The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG-M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG-M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC-MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH-mediated OXPHOS pathway, thereby inducing MG-M2 polarization, promoting neuronal survival and exerting an anti-AD role is elucidated.
Asunto(s)
Desoxiadenosinas , Modelos Animales de Enfermedad , Microglía , Mitocondrias , Animales , Microglía/metabolismo , Microglía/efectos de los fármacos , Desoxiadenosinas/farmacología , Desoxiadenosinas/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Hexoquinasa/metabolismo , Hexoquinasa/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Reprogramación MetabólicaRESUMEN
PURPOSE: Microglia-neuron crosstalk is critically involved in synaptic plasticity and degeneration by releasing diverse mediators in Alzheimer's disease (AD). Therefore, determining contributors that modulate the systemic microenvironment is essential. Cordycepin (CCS) is a novel neuroprotective compound obtained from Cordyceps militaris. However, the anti-AD efficacy and potential mechanism of CCS treatment remain unclear. This study aimed to elucidate the microglia-neuron symphony in AD after CCS treatment and to explore the possible mechanisms of its neuroprotective efficacy. METHODS AND RESULTS: CCS treatment improved learning and memory impairment in 9-month-old APP/PS1 mice by behavioral tests. CCS polarized the microglia from M1 to M2, inhibited neuronal apoptosis and promoted synaptic remodeling accompanied by in vivo and in vitro upregulation of NGF. The cAMP-response element-binding protein (CREB) was also activated after MG-M2 polarization. Further, we verified that the sg3 promoter region of NGF (-1018 to -1011) is the key binding site for CREB-induced NGF transcription, which increased NGF expression and secretion. Finally, microglia-derived NGF was confirmed as an important mediator in microglia-neuron symphony to improve the neuronal microenvironment after CCS treatment. CONCLUSIONS: CCS improved the neuronal synaptic plasticity and senescence by promoting MG-M2 activation driven by CREB-induced NGF upregulation and facilitated symphony communication between the microglia and neuron in AD. This study provides a new perspective on the development of a novel strategy for anti-AD therapy and offers new targets for anti-AD drug development.
Asunto(s)
Enfermedad de Alzheimer , Plasticidad Neuronal , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Microglía/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
With the development of medicine, our research on Alzheimer's disease (AD) has been further deepened, but the mechanism of its occurrence and development has not been fully revealed, and there is currently no effective treatment method. Several studies have shown that apolipoprotein AI (ApoA-I) can affect the occurrence and development of Alzheimer's disease by binding to amyloid ß (Aß). However, the association between circulating levels of ApoA-I and AD remains controversial. We conducted a meta-analysis of 18 studies published between 1992 and 2017 to determine whether the ApoA-I levels in the blood and cerebrospinal fluid (CSF) are abnormal in AD. Literatures were searched in PubMed, EMBASE and Web of Science databases without language limitations. A pooled subject sample including 1,077 AD patients and 1,271 healthy controls (HCs) was available to assess circulating ApoA-I levels; 747 AD patients and 680 HCs were included for ApoA-I levels in serum; 246 AD patients and 456 HCs were included for ApoA-I levels in plasma; 201 AD patients and 447 HCs were included for ApoA-I levels in CSF. It was found that serum and plasma levels of ApoA-I were significantly reduced in AD patients compared with HCs {[standardized mean difference (SMD) = -1.16; 95% confidence interval (CI) (-1.72, -0.59); P = 0.000] and [SMD = -1.13; 95% CI (-2.05, -0.21); P = 0.016]}. Patients with AD showed a tendency toward higher CSF ApoA-I levels compared with HCs, although this difference was non-significant [SMD = 0.20; 95% CI (-0.16, 0.56); P = 0.273]. In addition, when we analyzed the ApoA-I levels of serum and plasma together, the circulating ApoA-I levels in AD patients was significantly lower [SMD = -1.15; 95% CI (-1.63, -0.66); P = 0.000]. These results indicate that ApoA-I deficiency may be a risk factor of AD, and ApoA-I has the potential to serve as a biomarker for AD and provide experimental evidence for diagnosis of AD. Systematic Review Registration: PROSPERO, identifier: 325961.
RESUMEN
Background: Early diagnosis and effective intervention are the keys to delaying the progression of Alzheimer's Disease (AD). Therefore, we aimed to identify new biomarkers for the early diagnosis of AD through bioinformatic analysis and elucidate the possible underlying mechanisms. Methods and Results: GSE1297, GSE63063, and GSE110226 datasets from the GEO database were used to screen the highly differentially expressed genes. We identified a potential biomarker, Platelet activating factor receptor (PTAFR), significantly upregulated in the brain tissue, peripheral blood, and cerebrospinal fluid of AD patients. Furthermore, PTAFR levels in the plasma and brain tissues of APP/PS1 mice were significantly elevated. Simultaneously, PTAFR could mediate the inflammatory responses to exaggerate the microenvironment, particularly mediated by the microglia through the IL10-STAT3 pathway. In addition, PTAFR was a putative target of anti-AD compounds, including EGCG, donepezil, curcumin, memantine, and Huperzine A. Conclusion: PTAFR was a potential biomarker for early AD diagnosis and treatment which correlated with the microglia-mediated microenvironment. It is an important putative target for the development of a novel strategy for clinical treatment and drug discovery for AD.
RESUMEN
Serum lipid levels such as triglyceride and cholesterol has been reported to play an important role in the pathophysiological process of Alzheimer disease (AD) and mild cognitive impairment (MCI). However, it still remains controversial in different studies. Here, we performed a meta-analysis to assess the importance of serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in AD and MCI patients. PubMed, China National Knowledge Infrastructure (CNKI) system database were used to identify 17 studies (10 AD-only + 4 MCI-only + 3 shared AD/MCI), including 2333 cases and 3615 healthy controls (HC). We found that compared with HC, both the serum TC levels [SMD = 0.58; 95%CI (0.25, 0.90); P = 0.001) and the serum LDL-C levels [SMD = 0.7780; 95%CI (0.3940, 1.1521); P = 0.000] were higher in cognitive impairment population (including AD and MCI) than those in HC, respectively. Furthermore, we analyzed the serum TC and LDL-C levels in AD and MCI patients. We found that the serum TC levels [SMD = 0.76; 95% CI (0.13, 1.40); P = 0.019]1 and the LDL-C levels [SMD = 1.40; 95% CI (0.70, 2.10; P = 0.000] were increased in AD patients. In the MCI patients, the serum TC levels [SMD = 0.30; 95%CI (0.01, 0.59); P = 0.041] had a significantly upward trend, while the LDL-C levels had no significant change, compared with HC subjects. However, there is no significant changes in HDL-C and TG levels in AD or MCI patients. Therefore, our results suggested that the elevated TC and LDL-C levels may be a potential risk factor for cognitive impairment.
Asunto(s)
Enfermedad de Alzheimer/sangre , LDL-Colesterol/sangre , Colesterol/sangre , Disfunción Cognitiva/sangre , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Triglicéridos/sangreRESUMEN
Background: Gastric cancer (GC) is a global leading source of cancer-associated deaths. Circular RNAs (circRNAs) are a new type of non-coding RNA and promising biomarkers for diagnosis of multiple diseases such as cancer.Methods: Circ-PRMT5 expression was validated in 90 GC patient tissues and 6 different GC cells by qRT-PCR. Sublocalization of circ-PRMT5 in GC cells was determined in isolated nuclear and cytoplasmic RNAs. CircInteractome and miRanda were used to predict binding sites between circ-PRMT5 with micRNAs, and micRNAs with target mRNA. The correlation between genes was determined by the Pearson correlation analysis. The molecular mechanism was demonstrated by RNA in vivo precipitation, point mutation, luciferase activity and rescue experiments.Results: Circ-PRMT5 expression was significantly higher in GC than in adjacent normal tissues, and GC patients with circ-PRMT5 high expression had shorter survival times. Functionally, circ-PRMT5 silence inhibited GC cell growth and invasion. Mechanism analysis showed that circ-PRMT5 sponged miR-145/miR-1304 to upregulate MYC expression and GC development.Conclusion: Our findings demonstrated that circ-PRMT5 function as an oncogene in GC patients by targeting miR-145/miR-1304/MYC axis. High circ-PRMT5 expression may provide a poor prognostic indicator of survival in GC patients and targeting circ-PRMT5/miR-145/miR-1304/MYC axis may be a novel therapeutic strategy for GC.