Interaction between Aß and tau on reversion and conversion in mild cognitive impairment patients: After 2-year follow-up.

Background: The role of amyloid-ß (Aß) and tau in reversion and conversion in patients with mild cognitive impairment (MCI) remains unclear. This study aimed to investigate the influence of cerebrospinal fluid (CSF) Aß and tau on reversion and conversion and the temporal sequence of their pathogenicity in MCI patients. Methods: 179 MCI patients were recruited from the Alzheimer's Disease Neuroimaging Initiative database and classified into two groups based on cognitive changes after follow-up: reversal group (MCI to cognitively normal) and conversion group (MCI to Alzheimer's disease). CSF biomarkers and cognitive function were measured at baseline and 2-year follow-up. Partial correlation was used to analyze the association between CSF biomarkers and cognitive function, and multivariable logistic regression to identify independent risk factors for cognitive changes at baseline and 2-year follow-up. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive ability of these risk factors for cognitive changes. Results: The differences in cognitive function and CSF biomarkers between the two groups remained consistent with baseline after 2-year follow-up. After controlling for confounding variables, there was still a correlation between CSF biomarkers and cognitive function at baseline and 2-year follow-up. Multivariable regression analysis found that at baseline, only Aß level was independently associated with cognitive changes, while Aß and tau were both predictive factors after 2-year follow-up. ROC curve analysis revealed that the combination of Aß and tau [area under the curve (AUC) 0.91, sensitivity 84%, specificity 86%] in predicting cognitive changes after 2-year follow-up had better efficacy than baseline Aß alone (AUC 0.81). Conclusion: Aß may precede Tau in causing cognitive changes, and the interaction between the two mediates cognitive changes in patients. This study provides new clinical evidence to support the view that Aß pathology precedes tau pathology, which together contribute to the changes in cognitive function.

A metabolome atlas of mouse brain on the global metabolic signature dynamics following short-term fasting.

Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity.

PURPOSE: Recent studies have reported important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). Here, we tested the antitumor activity of a Dopamine receptor D1 (DRD1) agonist, either alone or in combination with temozolomide (TMZ) on GBM cells. METHODS: Immunofluorescence, immunohistochemistry and Western blotting were used to detect dopamine receptor expression in primary human GBM tissues. In addition, clinical data of GBM patients downloaded from The Cancer Genome Atlas (TCGA) were analyzed. Image-based tracking analysis of LC3 using a mCherry-eGFP-LC3 plasmid was utilized to monitor autophagic flux. Transmission electron microscopy (TEM) was used to visualize aggregation of autophagosomes/autolysosomes. Finally, DRD1 agonist (SKF83959)-induced inhibition of GBM growth was assessed in vitro and in vivo. RESULTS: Positive DRD1 expression was observed in human GBM tissues and found to be related with a good clinical outcome. DRD1 activation specifically inhibited GBM cell growth and significantly disrupted autophagic flux, which led to tumor cell death. Moreover, we found that DRD1 agonist treatment inhibited auto-lysosomal degradation in GBM cells and that this process was calcium overload dependent and related to inhibition of mammalian target of rapamycin (mTOR). Finally, we found that DRD1 agonist and TMZ co-treatment yielded a synergistic therapeutic effect both in vivo and in vitro. CONCLUSIONS: From our data we conclude that DRD1 activation inhibits GBM cell growth and may serve as an alternative avenue for the design of future GBM therapies.

Therapeutic effects of hirsutella sinensis on the disease onset and progression of amyotrophic lateral sclerosis in SOD1G93A transgenic mouse model.

AIMS: Although the pathophysiology of amyotrophic lateral sclerosis (ALS) is still not completely understood, the deregulated microglia polarization and neuroinflammation have been shown to contribute to the pathogenesis and progression of this disease. In the present study, we aimed to determine whether hirsutella sinensis (HS) could reduce neuroinflammatory and pathological changes in the spinal cord of SOD1G93A model mice of ALS and consequently ameliorate disease onset and progression. METHODS: SOD1G93A mice were chronically treated with HS by gavage. Their lifespan was recorded, and motor behavior was evaluated by rotarod test. The pathological changes in skeletal muscles and motor neurons in spinal cords were assessed by immunofluorescent staining and hematoxylin-eosin staining. The microglia activation and neuroinflammation were determined by immunofluorescent staining and RT-PCR. RESULTS: Our data suggested that repeated HS administration prolonged the lifespan and extended disease duration of ALS mice without significant delay on disease onset. HS ameliorated the pathological changes in the motor neurons and gastrocnemius muscles. Moreover, HS promoted the transition of microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype in the spinal cord of ALS mice. CONCLUSION: All these findings indicate that HS may serve as a potential therapeutic candidate for the treatment of ALS.

Exercise and Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the world. Unfortunately, most of the currently used clinical therapies against PD are symptomatic and there is still no remedy can stop disease progression. Collective evidence shows that various kinds of exercise may reduce the risk of PD and do have positive impacts on both motor and nonmotor symptoms of PD. Additionally, exercise can also ameliorate the side effects such as wearing-off and dyskinesia induced by anti-PD therapeutics. In parallel with its benefits in ameliorating clinical symptoms, exercise modulates a range of supporting systems for brain maintenance and plasticity including neurogenesis, synaptogenesis, enhanced metabolism and angiogenesis. Exercise provides all these broad benefits on PD through inhibiting oxidative stress, repairing mitochondrial damage, and promoting the production of growth factors. Moreover, exercise reduces risk of other geriatric diseases such as diabetes, hypertension and cardiovascular disease, which may also contribute to PD pathogenesis. In summary, exercise is increasingly considered to be a complementary strategy to PD medications. In this chapter, we summarize the recent research progress on the beneficial effects of exercise on PD, discuss the underlying mechanisms, and highlight the promising prospects of exercise for antiparkinsonian therapy.

Alteration in sleep architecture and electroencephalogram as an early sign of Alzheimer's disease preceding the disease pathology and cognitive decline.

OBJECTIVE: The present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD). BACKGROUND AND RATIONALE: Sleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease. HISTORICAL EVOLUTION: Sleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD. UPDATED HYPOTHESIS: Based on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage. EARLY EXPERIMENTAL DATA: Our data suggested that AßPPswe/PS1ΔE9 transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology. FUTURE EXPERIMENTS AND VALIDATION STUDIES: Future experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow-up studies in high-risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated. MAJOR CHALLENGES FOR THE HYPOTHESIS: Studies on human participants with early stage of AD, especially the follow-up studies on the presymptomatic elderly in a large population, are difficult and time-consuming. LINKAGE TO OTHER MAJOR THEORIES: Our hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression.

Graphene Oxide Nanocolloids Induce Autophagy-Lysosome Dysfunction in Mouse Embryonic Stem Cells.

In this study, we aimed to investigate the in vitro impacts and mechanisms of graphene oxide (GO) nanocolloids on autophagy in mouse embryonic stem cells (mESCs). Our results showed that GO nanocolloids treatment induced autophagosome accumulation in mESCs. In addition, we found that this effect was mediated by the blockade of autophagic flux rather than autophagic induction, as evidenced by the elevated autophagic substrate SQSTM1/p62 level and LC3B turn over. Moreover, our data further revealed that GO nanocolloids disrupted autophagic flux by impairing lysosomal function, including lysosomal alkalinization and lysosome membrane permeabilization. These results indicate that GO nanocolloids can block autophagic flux in mESCs via autophagy-lysosome dysfunction. Our findings may reveal the putative mechanism of GO nanocolloids-modulated autophagy and provide experimental evidence for the importance of future safety evaluation of nanomaterials.

Acute Hypoxia Induced an Imbalanced M1/M2 Activation of Microglia through NF-κB Signaling in Alzheimer's Disease Mice and Wild-Type Littermates.

Alzheimer's disease (AD) is the most common neurodegenerative disease mainly caused by abnormal tau phosphorylation, amyloid ß (Aß) deposition and neuroinflammation. As an important environmental factor, hypoxia has been reported to aggravate AD via exacerbating Aß and tau pathologies. However, the link between hypoxia and neuroinflammation, especially the changes of pro-inflammatory M1 or anti-inflammation M2 microglia phenotypes in AD, is still far from being clearly investigated. Here, we evaluated the activation of microglia in the brains of APPswe/PS1dE9 transgenic (Tg) mice and their wild type (Wt) littermates, after a single episode of acute hypoxia (24 h) exposure. We found that acute hypoxia activated M1 microglia in both Tg and Wt mice as evidenced by the elevated M1 markers including cluster of differentiation 86 (CD86), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2) and CCL3. In addition, the markers of M2 microglia phenotype (arginase-1 (Arg-1), CD206, IL-4 and IL-10) were decreased after acute hypoxia exposure, suggesting an attenuated M2 phenotype of microglia. Moreover, the activation of microglia and the release of cytokines and chemokines were associated with Nuclear factor-κB (NF-κB) induction through toll-like receptor 4 (TLR4). In summary, our findings revealed that acute hypoxia modulated microglia M1/M2 subgroup profile, indicating the pathological role of hypoxia in the neuroinflammation of AD.