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Fine particulate matter 2.5 (PM2.5), one of the main components of air pollutants, seriously threatens human health. Possible neuronal dysfunction induced by PM2.5 has received extensive attention. However, there is little evidence for the specific biochemical mechanism of neuronal injury induced by PM2.5. Moreover, the pathway for PM2.5 transport from peripheral circulation to the central nervous system (CNS) is still unclear. In the current work, C57BL/6 mice were chronically exposed to ambient PM2.5 for 3, 6, 9, and 12 months. Exposure to ambient PM2.5 resulted in a significant reduction of cognitive ability in mice by Morris water maze test. PM2.5 exposure induced a neuroinflammatory reaction after cognitive impairment, while inflammation in the hypothalamus and olfactory bulb tissue occurred earlier. The expression levels of integrity tight junction proteins in the blood-brain barrier (BBB) were reduced by PM2.5 exposure. Pulmonary inflammation occurred much earlier and diminished at later stage of PM2.5 exposure. The results indicated that chronic exposure to ambient PM2.5 led to cognitive decline in mice; CNS dysfunction may be due to neuroinflammatory reactions; the reduced integrity of the BBB allowed the influence of pulmonary inflammation to neuronal alterations. The work may provide promising therapeutic or preventive targets for air pollution-induced neurodegenerative disease.

PM2.5 particles are widely believed to be associated with respiratory and cardiovascular diseases. However, recent studies have reported that PM2.5 may be associated with neurodegenerative diseases. The exact mechanism by which PM2.5 mediates neurotoxicity and cognitive dysfunction is still unclear. In the current work, we collected evidence supporting the association between PM2.5 exposure and development of neurodegenerative disorders. Evidence from epidemiological investigations, animal experiments, and ex vivo cell experiments showed that PM2.5 exposure may lead to neuroinflammation, oxidative stress, mitochondrial dysfunction, neuronal apoptosis, synaptic damage and ultimately neurodegenerative diseases.

Background: Alzheimer's disease (AD) is one of the most common irreversible degenerative diseases of the central nervous system. Recent studies have found that patients with AD generally experienced abnormal glucose metabolism. Xylitol is a functional sugar alcohol, which has been reported to regulate glucose metabolism. Objective: The present study was designed to determine whether xylitol can alleviate cognitive impairment in AD mice. Methods: In the current research, 5% xylitol was supplemented in diet to treat APP/PS1 transgenic AD mice for 2 months. Cognitive ability was measured by Morris water maze, anxiety-like behaviors was examined by open-field experiment. Hippocampal cellular apoptosis and mitochondria pathway related apoptotic proteins were tested by TUNEL staining and immunoblotting, respectively. By LC-MS, plasma levels of glucose metabolism intermediates and related amino acids were evaluated. Results: Results showed that xylitol could significantly ameliorate the anxiety-like activity in AD mice, by at least partially regulating expression levels of mitochondrial pathway related apoptotic proteins. The participation of xylitol regulated glucose metabolism may play the important role in the process. Conclusion: The current study suggests that xylitol may be a potential candidate for improving neuropsychiatric behavior in AD by regulating the levels of TCA cycle intermediates and related amino acids in glucose metabolism.

PM2.5 exposure is considered harmful to central nerve system, while the specific biochemical mechanism underlying is still unrevealed. Neuronal apoptosis is believed the crucial event in pathogenesis of neurodegenerative diseases, but evidence supporting neuronal apoptosis as the mechanism for PM2.5 exposure induced neuronal injury is insufficient. S-adenosylmethionine decarboxylase 1 (AMD1) and its related spermidine synthesis have been shown to associate with cellular apoptosis, but its role in PM2.5 exposure induced neuronal apoptosis was rarely reported. The current study was aimed to better understand contribution of AMD1 activity and spermidine in PM2.5 exposure induced neuronal apoptosis. Sixteen C57BL/6 male mice were randomly divided and kept into ambient PM2.5 chamber or filtered air chamber for 6 months to establish the mouse model of whole-body ambient PM2.5 chronic exposure. In parallel, PC12 cells and primary hippocampal neurons were applied for various concentrations of PM2.5 treatment (0, 25, 50, 100, 200, and 400 μg/mL) to explore the possible cellular and molecular mechanism which may be critically involved in the process. Results showed that PM2.5 exposure triggered neuronal apoptosis with increased expression of Bax/Bcl-2 and cleaved caspase-3. PM2.5 exposure reduced AMD1 expression and spermidine synthesis. AMD1 inhibition could mimic PM2.5 exposure induced neuronal apoptosis. Spermidine supplementation rescued against neurotoxicity and inhibited PM2.5 induced apoptosis via impaired depolarization of mitochondrial membrane potential and reduced mitochondrial apoptosis related proteins. In summary, our work demonstrated that exposure to PM2.5 led to neuronal apoptosis, which may be the key event in the process of air pollution induced neurodegenerative diseases. AMD1 and spermidine associated with neuronal apoptosis induced by PM2.5 exposure, which was at least partially dependent on mitochondria mediated pathway.

N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

PM2.5 particles in air pollution have been widely considered associated with respiratory and cardiovascular diseases. Recent studies have shown that PM2.5 can also cause central nervous system (CNS) diseases, including a variety of neurodegenerative diseases, such as Alzheimer's disease (AD). Activation of microglia in the central nervous system can lead to inflammatory and neurological damage. PM2.5 will reduce the methylation level of DNA and affect epigenetics. PM2.5 enters the human body through a variety of pathways to have pathological effects on CNS. For example, PM2.5 can destroy the integrity of the blood-brain barrier (BBB), so peripheral systemic inflammation easily crosses BBB and reaches CNS. The olfactory nerve is another way for PM2.5 particles to enter the brain. Surprisingly, PM2.5 can also enter the gastrointestinal tract, causing imbalances in the intestinal microecology to affect central nervous system diseases. The current work collected and discuss the mechanisms of PM2.5-induced CNS damage and PM2.5-induced neurodegenerative diseases.

Cobalamin degrades in the presence of light and heat, which causes spectral changes and loss of coenzyme activity. In the presence of beta-lactoglobulin or alpha-lactalbumin, the thermal- and photostabilities of adenosylcobalamin (ADCBL) and cyanocobalamin (CNCBL) are increased by 10–30%. Similarly, the stabilities of ADCBL and CNCBL are increased in the presence of whey proteins by 19.7% and 2.2%, respectively, when tested in gastric juice for 2 h. Due to the limited absorption of cobalamin during digestion, excess cobalamin can enter the colon and modulate the gut microbiome. In a colonic model in vitro, supplementation with cobalamin and whey enhanced the proportions of Firmicutes and Bacteroidetes spp. and reduced those of Proteobacteria spp., which includes pathogens such as Escherichia and Shigella spp., and Pseudomonas spp. Thus, while complex formation could improve the stability and bioavailability of cobalamin, these complexes might also mediate gut microecology to influence human nutrition and health.

Background: Fine particle (Particulate matter 2.5, PM2.5), as the primary ambient pollutant, is considered harmful to some neurodegenerative diseases, while the specific biochemical mechanism underlying is still unrevealed. Neuronal apoptosis is believed the crucial event in neurodegenerative pathogenesis, but evidence supporting neuronal apoptosis as PM2.5 induced neuronal injury is insufficient. S-adenosylmethionine decarboxylase 1 (AMD1) and its related spermidine synthesis have been shown to participate in cellular apoptosis, but its role in PM2.5 exposure induced neuronal apoptosis was rarely reported. To better understand contribution of AMD1 activity and spermidine in PM2.5 exposure induced neuronal apoptosis, may provide novel therapeutic and preventive targets for air pollution associated neurodegenerative diseases.Methods: In the current work, sixteen C57BL/6 male mice were randomly divided into ambient PM2.5 chamber or filtered air chamber, and the mouse model of whole-body ambient PM2.5 chronic exposure was established. Behavioral and cognitive ability, together with corresponding biomedical index were recorded and tested to evaluated neurotoxicity by PM2.5 exposure in mice. In parallel, PC12 cells and primary hippocampal neurons were applied for PM2.5 treatment to explore the possible cellular and molecular mechanism which may be critically involved in the process. AMD1 activity and cellular spermidine content were modulated by pharmacological approach to examine their participation in PM2.5 triggered neuronal apoptosis, followed by better examination of typical index for mitochondrial membrane potential and mitochondrial-mediated apoptosis pathway signaling.Results: Chronic ambient PM2.5 exposure attenuated spatial learning and memory ability, and triggered neuronal apoptosis together with increased expression of apoptosis-related Bax/Bcl-2 and cleaved caspase-3. PM2.5 exposure impaired AMD1 expression and spermidine synthesis. AMD1 inhibition could mimick PM2.5 exposure induced neuronal apoptosis. Spermidine supplementation rescued against neurotoxicity and inhibited PM2.5 induced apoptosis, in which mitochondrial pathway signaling.Conclusions: Chronic real-time exposure to ambient PM2.5 led to the reduced the ability of spatial learning and memory in mice. Neuronal apoptosis was the key event in the process of neurodegenerative development induced by PM2.5 exposure. AMD1 and spermidine participated in neuronal apoptosis induced by PM2.5 exposure, which was at least partially dependent on mitochondria mediated pathway.

Globally, Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly population, the hallmark of which is amyloid β (Aβ) peptide. Energy metabolism and AD pathogenesis are believed to influence one another. Different cholesterol levels are thought to influence various steps in neurotoxic Aβ generation, including amyloid precursor protein (APP) proteolysis and the corresponding activities of α-, β-, and γ-secretases. In addition, cholesterol has been proved to mediate Aβ metabolism, such as its fibrillation, transportation, degradation, and clearance processes. The current review discusses in detail the intimate interaction between the cholesterol level and the various aspects of APP proteolysis and Aβ metabolism.

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Background Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear. Results In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1β-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling. Conclusions Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.