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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and currently there are no available treatments. Alongside the conventional Aβ and tau hypotheses, neuroinflammation and metabolism disruption have also been regarded as crucial hallmarks of AD. In this study, a novel Chinese formula Nao Tan Qing (NTQ) was developed and shown to improve AD. In vivo experiments showed that NTQ significantly mitigated cognitive impairment, Aβ burden and neuroinflammation in a transgenic AD mouse model (5×FAD). Network pharmacology results revealed that the active components of NTQ could target inflammatory and metabolic pathways. In addition, hippocampal transcriptomics suggested that NTQ regulated signaling pathways related to inflammation and lipid metabolism. Consistently, serum metabolomics further indicated that NTQ could modulate glycolipid metabolism. In summary, a combination of systems pharmacology analysis and biological validation study demonstrates that NTQ could alleviate behavioral abnormality and pathological alterations of AD by targeting glycolipid metabolism and neuroinflammation, and is accordingly a potential therapeutic agent for AD.

The neuroprotective effects of Coeloglossum viride var. bracteatum extract (CE) was investigated in a mouse model of AD. We found that CE improved cognitive deficits in 5xFAD mice in MWM and Y-maze behavioral tests. Also, antioxidant levels in serum and brain were normalized and peroxidation product MDA was reduced after CE treatment compared to untreated 5xFAD mice. Similarly, levels of pro-inflammatory factors such as TNF-α, IL-6 and IL-1β were reduced and anti-inflammatory factor IL-10 was increased. CE restored levels of BDNF and FGF2, as well as the signaling regulators Akt, TrkB and the apoptotic factors Bcl-2 and cleaved-Caspase-3. In addition, the RIP1/RIP3/MLKL inflammatory signaling pathway and necroptosis were inhibited, the RIP1 inhibitor TBK1 was restored and Aβ deposition was reduced in hippocampus and prefrontal cortex of 5xFAD mice. Thus, CE is effective in improving cognitive dysfunction in AD mouse models and may be a potential therapeutic agent.

Astrocytes are an abundant subgroup of cells in the central nervous system (CNS) that play a critical role in controlling neuronal circuits involved in emotion, learning, and memory. In clinical cases, multiple chronic brain diseases may cause psychosocial and cognitive impairment, such as depression and Alzheimer’s disease (AD). For years, complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability, resulting in gradual loss of self-care ability, lower life qualities, and vast burden on human society. Interestingly, correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease. As a kind of multifunctional glial cell in the CNS, astrocytes maintain physiological function via supporting neuronal cells, modulating pathologic niche, and regulating energy metabolism. Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD. We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD, with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.

The pro-inflammatory activation of microglia is a hallmark of Alzheimer’s disease (AD), and this process is known to involve a switch in energy metabolism from oxidative phosphorylation (OXPHOS) towards glycolysis. Here, we show how a positive feedback loop in microglia—comprising metabolic, histone lactylation, and transcriptional layers—drives AD pathogenesis, and we demonstrate that inhibiting this vicious cycle in microglia can ameliorate Aβ burden and cognitive deficits in AD model mice. After first detecting elevated histone lactylation in both AD model (5XFAD) mice and AD patient brains, we observed that H4K12la levels are elevated specifically in Aβ plaque-adjacent microglia. We subsequently found that this lactate-dependent histone modification is enriched at the promoters of glycolytic genes (e.g., Pkm). We confirmed that this enrichment activates transcription and thereby increases glycolysis activity, and ultimately demonstrate that a glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD. Pharmacologic inhibition of PKM2 attenuated microglial activation, and microglia-specific ablation of Pkm2 improved spatial learning and memory in AD mice. Thus, beyond demonstrating a role for histone lactylation in a neurodegenerative disease and showing how multi-layered regulatory impacts attend altered glucose metabolism in microglia, our study illustrates that disrupting a positive feedback loop may support the development of innovative AD therapies.

Genetic variants conferring risk for schizophrenia (SCZ) have been extensively studied, but the role of posttranscriptional mechanisms in SCZ is not well studied. Here we performed the first genome-wide microRNA (miRNA) expression profiling in serum-derived exosome from 49 first-episode, drug-free SCZ patients and 46 controls and identified miRNAs and co-regulated modules that were perturbed in SCZ. Putative targets of these SCZ-affected miRNAs were enriched strongly for genes that have been implicated in protein glycosylation and were also related to neurotransmitter receptor and dendrite (spine) development. We validated several differentially expressed blood exosomal miRNAs in 100 SCZ patients as compared with 100 controls by quantitative reverse transcription-polymerase chain reaction. The potential regulatory relationships between several SCZ-affected miRNAs and their putative target genes were also validated. These include hsa-miR-206, which is the most upregulated miRNA in the blood exosomes of SCZ patients and that previously reported to regulate brain-derived neurotrophic factor expression, which we showed reduced mRNA and protein levels in the blood of SCZ patients. In addition, we found 11 miRNAs in blood exosomes from the miRNA sequence data that can be used to classify samples from SCZ patients and control subjects with close to 90% accuracy in the training samples, and approximately 75% accuracy in the testing samples. Our findings support a role for exosomal miRNA dysregulation in SCZ pathophysiology and provide a rich data set and framework for future analyses of miRNAs in the disease, and our data also suggest that blood exosomal miRNAs are promising biomarkers for SCZ.

The excessive release and accumulation of glutamate in the brain is known to be associated with excitotoxicity. CE, an extract derived from the plant Coeloglossum viride var. Bracteatum, exerted neuroprotective effects against amyloid toxicity and oxidative stress in cortical neurons. The aims of this study are to examine whether CE also attenuates glutamate neurotoxicity in rat primary cultured cortical neurons and to determine the effect of CE in vivo. According to the results of MTT, LDH release, and TUNEL assays, the CE treatment significantly reduced glutamate-induced neurotoxicity in a dose-dependent manner. Moreover, the protective effects of CE were blocked by an Akt inhibitor, LY294002, suggesting that the PI3K/Akt signalling pathway is involved in the neuroprotective effects of CE. In addition, CE might regulate the PKC-GluA2 axis to prevent neuronal apoptosis. CE also protected against dopaminergic neuronal loss in a mouse model of MPTP-induced PD. Based on our results, CE exerted neuroprotective effects both in vitro and in vivo, thus providing a potential therapeutic target for the treatment or prevention of neurodegeneration.

The present study explored the neuroprotective effect ofCoeloglossum viridevar. bracteatum extract (CE) against oxidative stress in rat cortical neurons. The results demonstrated that administration of CE inhibited hydrogen peroxide-induced neurotoxicity tested by MTT, LDH release, and TUNEL assays. We further found that CE inhibited the activation of caspase-3 (Csp3) induced by hydrogen peroxide. Moreover, CE was found to reverse the hydrogen peroxide-induced downregulation of active AKT and Bcl-2. We then showed that the neuroprotective effect of CE was blocked by adding the AKT inhibitor, Ly294002. Thus, our data strongly indicated that CE played a neuroprotective role against oxidative stress-induced neurotoxicity.