GuanXinNing Tablet Attenuates Alzheimer’s Disease via Improving Gut Microbiota, Host Metabolites, and Neuronal Apoptosis in Rabbits

Based on accumulating evidence, Alzheimer’s disease (AD) is related to hypercholesterolemia, gut microbiota, and host metabolites. GuanXinNing Tablet (GXN) is an oral compound preparation composed of two Chinese herbs, Salvia miltiorrhiza Bge. and Ligusticum chuanxiong Hort., both of which exert neuroprotective effects. Nevertheless, the effect of GXN on AD is unknown. In the present study, we investigated whether GXN alters cholesterol, amyloid-beta (Aβ), gut microbiota, serum metabolites, oxidative stress, neuronal metabolism activities, and apoptosis in an AD model rabbit fed a 2% cholesterol diet. Our results suggested that the GXN treatment significantly reduced cholesterol levels and Aβ deposition and improved memory and behaviors in AD rabbits. The 16S rRNA analysis showed that GXN ameliorated the changes in the gut microbiota, decreased the Firmicutes/Bacteroidetes ratio, and improved the abundances of Akkermansia and dgA-11_gut_group. 1H-NMR metabolomics found that GXN regulated 12 different serum metabolites, such as low-density lipoprotein (LDL), trimethylamine N-oxide (TMAO), and glutamate (Glu). In addition, the 1H-MRS examination showed that GXN remarkably increased N-acetyl aspartate (NAA) and Glu levels while reducing myo-inositol (mI) and choline (Cho) levels in AD rabbits, consequently enhancing neuronal metabolism activities. Furthermore, GXN significantly inhibited oxidative stress and neuronal apoptosis. Taken together, these results indicate that GXN attenuates AD via improving gut microbiota, host metabolites, and neuronal apoptosis.

Mechanistic model-driven exometabolomic characterisation of human dopaminergic neuronal metabolism

Patient-derived cellular models are a powerful approach to study human disease, especially neurodegenerative diseases, such as Parkinson's disease, where affected primary neurons, e.g., substantia nigra dopaminergic neurons, are almost inaccessible. Starting with a comprehensive generic reconstruction of human metabolism, Recon3D, we generated a high-quality, constraint-based, genome-scale, in silico model of human dopaminergic neuronal metabolism (iDopaNeuro1). It is a synthesis of extensive manual curation of the biochemical literature on neuronal metabolism, together with novel, quantitative, transcriptomic and targeted exometabolomic data from human stem cell-derived, midbrain-specific, dopaminergic neurons in vitro. Thermodynamic constraint-based modelling with iDopaNeuro1 is qualitatively accurate (92% correct) and quantitatively accurate (Spearman rank 0.7) at predicting metabolite secretion or uptake, given quantitative exometabolomic constraints on uptakes, or secretions, respectively. iDopaNeuro1 is also qualitatively accurate at predicting the consequences of metabolic perturbations, e.g., complex I inhibition (Spearman rank 0.69) in a manner consistent with literature on monogenic mitochondrial Parkinson's disease. The iDopaNeuro1 model provides a foundation for a quantitative systems biochemistry approach to metabolic dysfunction in Parkinson's disease. Moreover, the plethora of novel mathematical and computational approaches required to develop it are generalisable to study any other disease associated with metabolic dysfunction.

Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: The role of Miro1

Stroke-induced cerebral ischemia is a major cause of death and disability. The disruption of blood flow results in neuronal and glial cell death leading to brain injury. Reperfusion restores oxygen to the affected tissue, but can also cause damage through an enhanced oxidative stress and inflammatory response. This study examines mitochondrial transfer from MSC to neurons and the role it plays in neuronal preservation after oxidant injury. We observed the transfer of mitochondria from MSC to mouse neurons in vitro following hydrogen peroxide exposure. The observed transfer was dependent on cell-to-cell contact and led to increased neuronal survival and improved metabolism. A number of pro-inflammatory and mitochondrial motility genes were upregulated in neurons after hydrogen peroxide exposure. This included Miro1 and TNFAIP2, linking inflammation and mitochondrial transfer to oxidant injury. Increasing Miro1 expression in MSC improved the metabolic benefit of mitochondrial transfer after neuronal oxidant injury. Decreasing Miro1 expression had the opposite effect, decreasing the metabolic benefit of MSC co-culture. MSC transfer of mitochondria to oxidant-damaged neurons may help improve neuronal preservation and functional recovery after stroke.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder

Background Previous studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients. Methods A total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated. Results The decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients. Conclusions The findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

Neuronal Lipoprotein Lipase Deficiency alters Neuronal Function and Hepatic Metabolism

Background: The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL may be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Methods: Measures of glucose homeostasis in mice homozygous (NEXLPL-/-) and heterozygous (NEXLPL+/-) for neuronal LPL deficiency were compared to that of WT mice. A detailed analysis of hepatic glucose and lipid metabolism was also determined in NEXLPL+/- at 6-18 mo. To determine the effect of neuronal LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. In addition, we used Fluorescence Lifetime Imaging Microscopy (FLIM) as a novel method to visualize changes in neuronal metabolism following LPL-depletion directly in the PVN. Results: Here we show that despite obesity, mice with reduced neuronal LPL also show improved glucose tolerance and reduced hepatic lipid accumulation with aging, concomitant with reduced hepatic lipogenic gene expression (e.g. SCD1 and FADS2). Retroviral tracing and patch clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons lacking LPL. Quantification of the free versus bound Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD), revealed that LPL loss resulted in altered substrate utilization characterized by increased glucose utilization and TCA cycle flux. These findings were recapitulated by analysis of global metabolites from hypothalamic cell lines either deficient in, or over-expressing, LPL. Conclusions: Our data suggest that LPL is a novel feature of liver–related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to alter neuronal metabolism and function, leading to changes in systemic glucose metabolism including improved hepatic function with age.

Astrocytes: From the Physiology to the Disease

Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.

Extracellular Tau and Glymphatic Influx in Sleep and Anesthesia

Holth and colleagues recently examined how the sleep-wake cycle influence/regulate the amount of metabolic waste, mainly extracellular tau, in the brain (1). They report that interstitial fluid (ISF) tau in mice increases approximately by 90% during normal wakefulness versus sleep, and 100% during sleep deprivation (SD) as compared to 50% increase in CSF tau in humans. During SD, humans also registered increased levels of certain proteins like tau and synuclein with no significant changes in the levels of other neural proteins, suggesting some specificity in sleep/protein level interaction. This indicates that the above changes may be due to increased release of certain proteins rather than changes in global ISF clearance, which authors attribute to elevated neuronal metabolism/synaptic strength during SD and wakefulness (2). A major portion of the extracellular tau in the brain results from high neuronal/synaptic activity (2,3), but, we suggest, other potential factors may also add up to elevate the levels of tau normally present in ISF.