Arctigenin derivative A-1 ameliorates motor dysfunction and pathological manifestations in SOD1G93A transgenic mice via the AMPK/SIRT1/PGC-1α and AMPK/SIRT1/IL-1ß/NF-κB pathways.

AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated. METHODS: A-1 at 33.3 mg/kg was administrated in SOD1G93A transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. RESULTS: A-1 administration in SOD1G93A mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1ß, pIκBα/IκBα, and pNF-κB/NF-κB. CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1ß/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.

NMDAR (2C) deletion in astrocytes relieved LPS-induced neuroinflammation and depression.

The link between neuroinflammation and depression is a subject of growing interest in neuroscience and psychiatry; meanwhile, the precise mechanisms are still being unrevealed. However, glial cell activation, together with cytokine level elevation, suggests a connection between neuroinflammation and the development or exacerbation of depression. Glial cells (astrocytes) communicate with neurons via their extracellular neurotransmitter receptors, including glutamate receptors NMDARs. However, these receptor roles are controversial and enigmatic in neurological disorders, including depression. Therefore, we hypothesized whether NMDAR subnit NR2C deletion in the astrocytes exhibited anti-depressive effects concurrent with neuroinflammation prevention. To assess, we prepared astrocytic-NR2C knockout mice (G-2C: GFAPCre+Grin2Cflox/flox), followed by LPS administration, behavior tests, and biochemical analysis. Stimulatingly, astrocytic-NR2C knockout mice (G-2C) did not display depressive-like behaviors, neuroinflammation, and synaptic deficits upon LPS treatment. PI3K was impaired upon LPS administration in control mice (Grin2Cflox/flox); however, they were intact in the hippocampus of LPS-treated G-2C mice. Further, PI3K activation (via PTEN inhibition by BPV) restored neuroinflammation and depressive-like behavior, accompanied by altered synaptic protein and spine numbers in G-2C mice in the presence of LPS. In addition, NF-κB and JNK inhibitor (BAY, SP600125) treatments reversed the effects of BPV. Moreover, these results were further validated with an NR2C antagonist DQP-1105. Collectively, these observations support the astrocytic-NR2C contribution to LPS-induced neuroinflammation, depression, and synaptic deficits.

ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice.

Apolipoprotein E4 (ApoE4) is involved in the stress-response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg-ApoEtm1Unc Cdh18Tg( GFAP-APOE i4)1Hol /J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4-induced depression. LPS treatment significantly aggravated depression-like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin-1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria-related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria-associated protein and mitophagy defects, including PGC-1α, TFAM, p-AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.

Tetramethylpyrazine Nitrone alleviates D-galactose-induced murine skeletal muscle aging and motor deficits by activating the AMPK signaling pathway.

Tetramethylpyrazine nitrone (TBN), a novel derivative of tetramethylpyrazine (TMP) designed and synthesized by our group, possesses multi-functional mechanisms of action and displays broad protective effects in vitro and in animal models of age-related brain disorders such as stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD). In the present report, we investigated the effects of TBN on aging, specifically on muscle aging and the associated decline of motor functions. Using a D-galactose-induced aging mouse model, we found that TBN could reverse the levels of several senescence and aging markers including p16, p21, ceramides, and telomere length and increase the wet-weight ratio of gastrocnemius muscle tissue, demonstrating its efficacy in ameliorating muscle aging. Additionally, the pharmacological effects of TBN on motor deficits (gait analysis, pole-climbing test and grip strength test), muscle fibrosis (hematoxylin & eosin (HE), Masson staining, and αSMA staining), inflammatory response (IL-1ß, IL-6, and TNF-α), and mitochondrial function (ATP, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also confirmed in the D-galactose-induced aging models. Further experiments demonstrated that TBN alleviated muscle aging and improved the decline of age-related motor deficits through an AMPK-dependent mechanism. These findings highlight the significance of TBN as a potential anti-aging agent to combat the occurrence and development of aging and age-related diseases.

Exhaustive exercise decreases tau phosphorylation and modifies biological processes associated with the protein translation and electron transport chain in P301L tau transgenic mice.

Stress response is a fundamental mechanism for cell survival, providing protection under unfavorable conditions. Mitochondrial stress, in particular, can trigger mitophagy, a process that restores cellular health. Exhaustive exercise (EE) is a form of acute mitochondrial stress. The objective of this current study is to investigate the impact of EE on tau pathology in pR5 mice, as well as the potential underlying mechanisms. To evaluate this, we examined the levels of total and phosphorylated tau in the hippocampus of pR5 mice, both with and without EE treatment. Furthermore, the application of weighted correlation network analysis (WGCNA) was employed to identify protein modules associated with the phenotype following the proteomic experiment. The findings of our study demonstrated a significant decrease in tau phosphorylation levels upon EE treatment, in comparison to the pR5 group. Moreover, the proteomic analysis provided additional insights, revealing that the mitigation of tau pathology was primarily attributed to the modulation of various pathways, such as translation factors and oxidative phosphorylation. Additionally, the analysis of heatmaps revealed a significant impact of EE treatment on the translation process and electron transport chain in pR5 mice. Furthermore, biochemical analysis provided further confirmation that EE treatment effectively modulated the ATP level in pR5 mice. In conclusion, our study suggests that the observed decrease in tau phosphorylation resulting from EE treatment may primarily be attributed to its regulation of the translation process and enhancement of mitochondrial function.

Arctigenin attenuated spatial memory impairment in pR5 mice by regulating mitochondrial energy metabolism.

OBJECTIVES: Arctigenin (ATG) is a natural product with a variety of biological activity, which can improve the pathological changes of Alzheimer's disease (AD) model mice through multiple mechanisms. This study aims to further elucidate the potential mechanism by which ATG improves memory impairment in AD mice. METHODS: Here, we used pR5 mice as an experimental model, and ATG was administered continuously for 90 days. Novel object recognition, Y-maze, and Morris water maze were used to evaluate the therapeutic effect of ATG on memory impairment in AD mice. Immunohistochemical and immunofluorescence analyses were used to evaluate the effects of ATG on tau hyperphosphorylation and neuroinflammation, respectively. Finally, proteomics techniques were used to explore the possible mechanism of ATG. KEY FINDINGS: ATG significantly improved memory impairment in pR5 mice and inhibited tau phosphorylation in the hippocampus and neuroinflammation in the cortex. According to the proteomic analysis, the altered cognitive function of ATG was associated with the proteins of the tricarboxylic acid cycle and the electron transport chain. CONCLUSION: These results suggest that ATG is a potential therapeutic agent for diseases related to aberrant energy metabolism that can treat AD by improving mitochondrial function.

A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders.

Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R-NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R-NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.

Low-dose Cu exposure enhanced α-synuclein accumulation associates with mitochondrial impairments in mice model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that mainly affects the elder population, and its etiology is enigmatic. Both environmental risks and genetics may influence the development of PD. Excess copper causes neurotoxicity and accelerates the progression of neurodegenerative diseases. However, the underlying mechanisms of copper-induced neurotoxicity remain controversial. In this study, A53T transgenic α-synuclein (A53T) mice and their matching wild-type (WT) mice were treated with a low dose of copper (0.13 ppm copper chlorinated drinking water, equivalent to the copper exposure of human daily copper intake dose) for 4 months, and copper poisoning was performed on human A53T mutant SHSY5Y cells overexpressed with α-synuclein (dose of 1/4 IC50), to test the effects of copper exposure on the body. The results of the open field test showed that the moto function of Cu-treated mice was impaired. Proteomics revealed changes in neurodevelopment, transport function, and mitochondrial membrane-related function in Cu-treated WT mice, which were associated with reduced expression of mitochondrial complex (NDUFA10, ATP5A), dopamine neurons (TH), and dopamine transporter (DAT). Mitochondrial function, nervous system development, synaptic function, and immune response were altered in Cu-treated A53T mice. These changes were associated with increased mitochondrial splitting protein (Drp1), decreased mitochondrial fusion protein (OPA1, Mfn1), abnormalities in mitochondrial autophagy protein (LC3BII/I, P62), decreased dopamine neuron (TH) expression, increased α-synuclein expression, inflammatory factors (IL-6, IL-1ß, and TNF-α) release and microglia (Iba1) activation. In addition, we found that Cu2+ (30 µM) induced excessive ROS production and reduced mitochondrial ATP production in human A53T mutant α-synuclein overexpressing SHSY5Y cells by in vitro experiments. In conclusion, low-dose copper treatment altered critical proteins involved in mitochondrial, neurodevelopmental, and inflammatory responses and affected mitochondria's ROS and ATP production levels.

Chrysin prevents inflammation-coinciding liver steatosis via AMPK signalling.

OBJECTIVES: We aimed to elucidate the therapeutic potential of Chrysin (CN) against the high-fat diet (HFD) induced non-alcoholic fatty liver disease (NAFLD) and its mechanism. METHODS: To assess the hypothesis, NAFLD was induced in C57BL/6 mice by feeding a high-fat diet for up to two months, followed by CN administration (for three months). Liver injury/toxicity, lipid deposition, inflammation and fibrosis were detected via molecular and biochemical analysis, including blood chemistry, immunoimaging and immunoblotting. Moreover, we performed proteomic analysis to illuminate Chrysin's therapeutic effects further. KEY FINDINGS: CN treatment significantly reduced liver-fat accumulation and inflammation, ultimately improving obesity and liver injury in NAFLD mice. Proteomic analysis showed that CN modified the protein expression profiles in the liver, particularly improving the expression of proteins related to energy, metabolism and inflammation. Mechanistically, CN treatment increased AMP-activated protein and phosphorylated CoA (P-ACC). Concurrently, it reduced inflammation and inflammation activation by inhibiting NLRP3 expression. CONCLUSIONS: In summary, CN treatment reduced lipid metabolism by AMPK and inflammasome activation by NLRP3 inhibition, ultimately improving NAFLD progression. These findings suggest that CN could be a potential treatment candidate for the NFLAD condition.

Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.

BACKGROUND: A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells. RESULTS: We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice. CONCLUSION: These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.

The relative and interactive effects of urinary multiple metals exposure on hyperuricemia among urban elderly in China.

Objective: Independent and interactive effects of multiple metals levels in urine on the risk of hyperuricemia (HUA) in the elderly were investigated. Methods: A total of 6,508 individuals from the baseline population of the Shenzhen aging-related disorder cohort were included in this study. We detected urinary concentrations of 24 metals using inductively coupled plasma mass spectrometry, fitted unconditional logistic regression models, and the least absolute shrinkage and selection operator regression models for the selection of metals as well as unconditional stepwise logistic regression models and restricted cubic spline logistic regression models for assessing the associations of urinary metals and HUA risk, and finally applied generalized linear models to determine the interaction with urinary metals on the risk of HUA. Results: Unconditional stepwise logistic regression models showed the association between urinary vanadium, iron, nickel, zinc, or arsenic and HUA risk (all P < 0.05). We revealed a negative linear dose-response relationship between urinary iron levels and HUA risk (P overall < 0.001, P nonliner = 0.682), a positive linear dose-response relationship between urinary zinc levels and HUA risk (P overall < 0.001, P nonliner = 0.513), and an additive interaction relationship between urinary low-iron and high-zinc levels and HUA risk (RERI = 0.31, 95% CI: 0.03-0.59; AP = 0.18, 95%CI: 0.02-0.34; S = 1.76, 95%CI: 1.69-3.49). Conclusion: Urinary vanadium, iron, nickel, zinc, or arsenic levels were associated with HUA risk, and the additive interaction of low-iron (<78.56 µg/L) and high-zinc (≥385.39 µg/L) levels may lead to a higher risk of HUA.

Neuronal lack of PDE7a disrupted working memory, spatial learning, and memory but facilitated cued fear memory in mice.

BACKGROUND: PDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet. METHODS: Therefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches. RESULTS: PDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25. CONCLUSION: Altogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders.

Chromium [Cr(VI)] Exposure Causes Cytotoxicity of Human Bronchial Epithelial Cells (16-HBE) and Proteomic Alterations.

Hexavalent chromium [Cr(VI)] is a common industrial pollutant, and exposure may cause toxic effects in multiple organ systems and carcinogenesis, including lung cancer. However, the toxic effect of Cr(VI) on the respiratory system is poorly understood. In the present study, it was demonstrated that Cr(VI) exposure significantly decreased the viability of human bronchial epithelial cells (16-HBE) in a dose-dependent manner. Flow cytometry demonstrated that Cr(VI) enhanced the transition of 16-HBE cells from G1 to S phase and arrested S-phase progression. Reverse transcription-quantitative polymerase chain reaction analysis revealed a significant alteration in the expression of apoptosis-associated genes in Cr(VI)-treated 16-HBE cells. In addition, using two-dimensional fluorescence differential gel electrophoresis with mass spectrometry, 15 differentially expressed proteins (1 upregulated and 14 downregulated) were identified in 16-HBE cells with Cr(VI) treatment compared with controls. Functional classification revealed that these differentially expressed proteins were involved in apoptosis, cytoskeletal structure, and energy metabolism. In conclusion, these data suggested that Cr(VI) caused toxic effects in bronchial epithelial cells and the mechanisms may involve the abnormal expression of apoptosis-associated proteins, cytoskeletal proteins, and energy metabolism-associated proteins.

Natural Dietary Compound Xanthohumol Regulates the Gut Microbiota and Its Metabolic Profile in a Mouse Model of Alzheimer's Disease.

Discovering new and effective drugs for the treatment of Alzheimer's disease (AD) is a major clinical challenge. This study focuses on chemical modulation of the gut microbiome in an established murine AD model. We used the 16S rDNA sequencing technique to investigate the effect of xanthohumol (Xn) on the diversity of intestinal microflora in 2-month- and 6-month-old APP/PS1 mice, respectively. APP/PS1 and wild-type mice were treated by gavage with corn oil with or without Xn every other day for 90 days. Prior to and following treatment, animals were tested for spatial learning, cognitive and memory function. We found Xn reduced cognitive dysfunction in APP/PS1 mice and significantly regulated the composition and abundance of gut microbiota both in prevention experiments (with younger mice) and therapeutic experiments (with older mice). Differential microflora Gammaproteobacteria were significantly enriched in APP/PS1 mice treated with Xn. Nodosilineaceae and Rikenellaceae may be the specific microflora modulated by Xn. The penicillin and cephalosporin biosynthesis pathway and the atrazine degradation pathway may be the principal modulation pathways. Taken together, oral treatment with Xn may have a neuroprotective role by regulating the composition of intestinal microflora, a result that contributes to the scientific basis for a novel prophylactic and therapeutic approach to AD.

Anti-depressive-like behaviors of APN KO mice involve Trkb/BDNF signaling related neuroinflammatory changes.

Major depression disorder is a severe mental illness often linked with metabolic disorders. Adiponectin is an adipocyte-secreted circulatory hormone with antidiabetic and glucose/lipid modulation capacities. Studies have demonstrated the pathophysiological roles of adiponectin involved in various neurological disorders, including depression. However, the underlying mechanisms are poorly understood. Here we showed that adiponectin deprivation enhanced antidepressive-like behaviors in the LPS-induced model of depression. APN KO mice displayed increased cytokines (both pro and anti-inflammatory), accompanied by an impaired expression of adiponectin receptors (mRNA/protein level) and decreasing IBA-1 level in the cortex and primary microglia of LPS treated APN KO mice. Further, LPS-treatment significantly reduced p-NFκB expression in the microglia of APN KO mice. However, the Bay11-7082 treatment recovered p-NFκB expression in the cortex of APN KO mice in the presence of LPS. Interestingly, the antidepressant potentials of APN KO mice were abolished by TrkB antagonist K252a, IKK inhibitor Bay11-7082, and AdipoRon suggesting crosstalk between TrkB/BDNF signaling and NFκB in depression. Furthermore, the effects of Bay11-7082 were abolished by a TrkB/BDNF activator (7,8-DHF), indicating a critical role of TrkB/BDNF signaling. Taken together, these findings showed that dysregulated neuroinflammatory status and BDNF signaling might underlie the antidepressive-like behaviors of APN KO mice. NFκB elicited BDNF changes may be accountable for the pathogenesis of LPS induced depression, where APN might present an alternative therapeutic target for depressive disorders.

Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation.

Adiponectin (APN) deficiency has also been associated with Alzheimer-like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aß accumulation, and the Aß elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aß accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini-Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aß deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aß deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK-mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aß deposition and its associated pathophysiologies. To eliminate Aß both extra- and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.

Manganese exposure causes movement deficit and changes in the protein profile of the external globus pallidus in Sprague Dawley rats.

Manganese (Mn) is required for normal brain development and function. Excess Mn may trigger a parkinsonian movement disorder but the underlying mechanisms are incompletely understood. We explored changes in the brain proteomic profile and movement behavior of adult Sprague Dawley (SD) rats systemically treated with or without 1.0 mg/mL MnCl2 for 3 months. Mn treatment significantly increased the concentration of protein-bound Mn in the external globus pallidus (GP), as demonstrated by inductively coupled plasma mass spectrometry. Behavioral study showed that Mn treatment induced movement deficits, especially of skilled movement. Proteome analysis by two-dimensional fluorescence difference gel electrophoresis coupled with mass spectrometry revealed 13 differentially expressed proteins in the GP of Mn-treated versus Mn-untreated SD rats. The differentially expressed proteins were mostly involved in glycolysis, metabolic pathways, and response to hypoxia. Selected pathway class analysis of differentially expressed GP proteins, which included phosphoglycerate mutase 1 (PGAM1), primarily identified enrichment in glycolytic process and innate immune response. In conclusion, perturbation of brain energy production and innate immune response, in which PGAM1 has key roles, may contribute to the movement disorder associated with Mn neurotoxicity.

Loganin substantially ameliorates molecular deficits, pathologies and cognitive impairment in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease threatening the health of the elderly, but the available therapeutic and preventive drugs remain suboptimal. Loganin, an iridoid glycoside extracted from Cornus officinalis, is reported to have anti-inflammatory and memory-enhancing properties. This study is aimed to explore the influence of loganin on cognitive function in 3xTg-AD mice and the underlying mechanism associated with its neuroprotection. According to the results of behavioral tests, we found that administration of loganin could significantly alleviate anxiety behavior and improve memory deficits of 3xTg-AD mice. Furthermore, immunohistochemical analysis displayed that there were decreased Aß deposition in the hippocampus and cortex of 3xTg-AD mice treated with loganin compared with the control mice. Importantly, the Aß-related pathological change was mainly involved in altering APP expression and processing. And loganin was also found to reduce the levels of phosphorylated tau (i.e. pTauS396 and pTauS262) in 3xTg-AD mice. By performing 2D-DIGE combined with MALDI-TOF-MS/MS, we revealed 28 differentially expressed proteins in the 3xTg-AD mice treated with loganin compared with the control mice. Notably, 10 proteins largely involved in energy metabolism, synaptic proteins, inflammatory response, and ATP binding were simultaneously detected in 3xTg-AD mice compared to WT mice. The abnormal changes of energy metabolism (PAGM1 and ENO1), synaptic proteins (SYN2 and Cplx2), inflammatory response (1433Z) were verified by western blot. Overall, our study suggested that loganin could be used as a feasible candidate drug to ameliorate molecular deficits, pathologies and cognitive impairment for prevention and treatment of AD.