Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. The main hypotheses about the pathogenesis of AD include the hypothesis of β-amyloid protein, the hypothesis of abnormal phosphorylation of Tau protein, and the hypothesis of neuroinflammation. In recent years, environmental pollutants have been considered as an important factor in causing neurological dysfunction. Common environmental pollutants include heavy metals, pesticides, polychlorinated biphenyls, microplastics, and air pollutants, all of which have been proven to have neurotoxicity. In this review, we not only discussed epidemiological and animal experimental studies that link environmental pollution with AD, but also summarized the mechanisms of action of relevant toxins, providing insights for studying the interrelationships between environmental pollutants and AD.
Animals ; Alzheimer Disease/chemically induced* ; Environmental Pollutants/toxicity* ; Neurodegenerative Diseases ; Plastics ; Amyloid beta-Peptides/metabolism*

Amyloid β-protein(Aβ) deposition in the brain is directly responsible for neuronal mitochondrial damage of Alzheimer's disease(AD) patients. Mitophagy, which removes damaged mitochondria, is a vital mode of neuron protection. Ginsenoside Rg_1(Rg_1), with neuroprotective effect, has displayed promising potential for AD treatment. However, the mechanism underlying the neuroprotective effect of Rg_1 has not been fully elucidated. The present study investigated the effects of ginsenoside Rg_(1 )on the autophagy of PC12 cells injured by Aβ_(25-35) to gain insight into the neuroprotective mechanism of Rg_1. The autophagy inducer rapamycin and the autophagy inhi-bitor chloroquine were used to verify the correlation between the neuroprotective effect of Rg_1 and autophagy. The results showed that Rg_1 enhanced the viability and increased the mitochondrial membrane potential of Aβ-injured PC12 cells, while these changes were blocked by chloroquine. Furthermore, Rg_(1 )treatment increased the LC3Ⅱ/Ⅰ protein ratio, promoted the depletion of p62 protein, up-regulated the protein levels of PINK1 and parkin, and reduced the amount of autophagy adaptor OPTN, which indicated the enhancement of autophagy. After the silencing of PINK1, a key regulatory site of mitophagy, Rg_1 could not increase the expression of PINK1 and parkin or the amount of NDP52, whereas it can still increase the LC3Ⅱ/Ⅰ protein ratio and promote the depletion of OPTN protein which indicated the enhancement of autophagy. Collectively, the results of this study imply that Rg_1 can promote autophagy of PC12 cells injured by Aβ, and may reduce Aβ-induced mitochondrial damage by promoting PINK1-dependent mitophagy, which may be one of the key mechanisms of its neuroprotective effect.
Amyloid beta-Peptides/toxicity* ; Animals ; Ginsenosides/pharmacology* ; Humans ; Mitophagy/physiology* ; PC12 Cells ; Protein Kinases/metabolism* ; Rats ; Ubiquitin-Protein Ligases/metabolism*

Alzheimer's disease (AD) is one of the major neurodegenerative disorders of the elderly, which is characterized by the accumulation and deposition of amyloid-beta (Aβ) peptide in human brains. Oxidative stress and neuroinflammation induced by Aβ in brain are increasingly considered to be responsible for the pathogenesis of AD. The present study aimed to determine the protective effects of walnut peptides against the neurotoxicity induced by Aβ25-35 in vivo. Briefly, the AD model was induced by injecting Aβ25-35 into bilateral hippocampi of mice. The animals were treated with distilled water or walnut peptides (200, 400 and 800 mg/kg, p.o.) for five consecutive weeks. Spatial learning and memory abilities of mice were investigated by Morris water maze test and step-down avoidance test. To further explore the underlying mechanisms of the neuroprotectivity of walnut peptides, the activities of superoxide dismutase (SOD), glutathione (GSH), acetylcholine esterase (AChE), and the content of malondialdehyde (MDA) as well as the level of nitric oxide (NO) in the hippocampus of mice were measured by spectrophotometric method. In addition, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and IL-6 in the samples were determined using ELISA. The hippocampal expressions of inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF-κB) were evaluated by Western blot analysis. The results showed that walnut peptides supplementation effectively ameliorated the cognitive deficits and memory impairment of mice. Meanwhile, our study also revealed effective restoration of levels of antioxidant enzymes as well as inflammatory mediators with supplementation of walnut peptides (400 or 800 mg/kg). All the above findings suggested that walnut peptides may have a protective effect on AD by reducing inflammatory responses and modulating antioxidant system.
Acetylcholinesterase ; metabolism ; Alzheimer Disease ; drug therapy ; etiology ; Amyloid beta-Peptides ; toxicity ; Animals ; Female ; Glutathione ; metabolism ; Hippocampus ; drug effects ; metabolism ; Interleukins ; metabolism ; Juglans ; chemistry ; Male ; Malondialdehyde ; metabolism ; Maze Learning ; Memory Disorders ; drug therapy ; etiology ; Mice ; NF-kappa B ; metabolism ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Nitric Oxide ; metabolism ; Peptide Fragments ; toxicity ; Peptides ; pharmacology ; therapeutic use ; Plant Extracts ; pharmacology ; therapeutic use ; Superoxide Dismutase ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating β-amyloid (Aβ) toxicity in C. elegans model of Alzheimer's disease (AD). In order to better apply CBE as an anti-AD agent efficiently, we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity. As the level of Aβ toxicity and memory health are two major pathological parameters in AD, in the present study, we compared the effects of CBE on Aβ toxicity and memory health in the C. elegans AD model treated with preventive and therapeutic protocols. Our results revealed that CBE prominently showed the preventive efficacy, providing a basis for further investigation of these effects in mammals.
Alzheimer Disease ; drug therapy ; genetics ; metabolism ; psychology ; Amyloid beta-Peptides ; metabolism ; toxicity ; Animals ; Caenorhabditis elegans ; drug effects ; metabolism ; Dietary Supplements ; analysis ; Disease Models, Animal ; Female ; Fruit ; chemistry ; Humans ; Male ; Memory ; drug effects ; Plant Extracts ; administration & dosage ; Vaccinium macrocarpon ; chemistry

BACKGROUNDHyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway.

METHODSAD rats were induced by injecting β-amyloid 25-35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg-1·d-1 ), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues.

RESULTSMorris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761.

CONCLUSIONSOur results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons.

Alzheimer Disease ; chemically induced ; drug therapy ; physiopathology ; therapy ; Amyloid beta-Peptides ; toxicity ; Animals ; Disease Models, Animal ; Ginkgo biloba ; chemistry ; Hyperbaric Oxygenation ; Male ; Maze Learning ; drug effects ; Memory Disorders ; drug therapy ; therapy ; NF-kappa B ; metabolism ; Plant Extracts ; therapeutic use ; Rats ; Rats, Sprague-Dawley

Tongluo Xingnao effervescent tablet (TLXNET) is a patented prescription, which comes from modified Xionggui decoction and can improve cognitive function. However, its effect on the urine metabolites and anti-dementia mechanism in the dementia model rats induced by hippocampal injection with Aβ25-35 remains unclear. The experiment focused on the changes in trajectory and inter-relationship among the urinary metabolite of rats in the blank group, Aβ25-35 hippocampal injection dementia model group and the TLXNET intervention group, in order to determine theirs characteristic metabolic markers and explain the anti-dementia effect of TLX-NET base on the change of metabolic trajectory of these bio-markers. According to the experimental results, 5, 6-indolequinone, 4-hydroxyphenyl pyruvic acid (4-HPPA), cortisol and 3-thiosulfate lactic were preliminarily identified as the characteristic metabolic markers. They mainly participate in dopamine system, glucocorticoids and energy metabolic pathways. TLXNET can apparently downregulate the disturbances of metabolic trajectory of the four bio-markers. The experiment indicates that the dementia model induced by injecting Aβ25-3 into hippocampus has its characteristic endogenous metabolic markers in urine, and ELXNET can ameliorate dementia by down-regulating the disturbances of metabolic trajectory.
Amyloid beta-Peptides ; metabolism ; toxicity ; Animals ; Biomarkers ; urine ; Dementia ; drug therapy ; urine ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Hippocampus ; drug effects ; metabolism ; Humans ; Male ; Metabolomics ; Peptide Fragments ; metabolism ; toxicity ; Rats ; Rats, Sprague-Dawley ; Tablets ; administration & dosage ; Urine ; chemistry

OBJECTIVETo study the role of PI3K/Akt pathway in the neuroprotective effect of paeoniflorin on PC12 cells.

METHODThe paeoniflorin group (5, 10, 20 μmol · L(-1)) was pretreated for 30 min, and then added with Aβ25-35 (20 μmol · L(-1)) for interaction for 24 h. Inhibitor LY294002 (10 μmol · L(-1)) was pretreated for 30 min before the action of paeoniflorin (10 μmol · L(-1)). The MTT colorimetric method was used to detect the cell viability. The apoptosis rate was tested by the FITC-Annexin V/PI staining. The protein expression of p-AKT, Bax, Bcl-2 and cleaved caspase-3 protein were detected by Western blot analysis.

RESULTPaeoniflorin could significantly inhibit the Aβ25-35-induced PC12 cell toxicity and apoptosis. Its protection effect may be achieved by up- regulating AKT phosphorylation level, increasing Bcl-2 protein expression, reducing Bax protein expression, inhibiting the activation of caspase-3. Inhibitor LY294002 could weaken the above protective effects of paeoniflorin.

CONCLUSIONPaeoniflorin could activate PI3K/Akt signaling pathway to protect the PC12 cell injury induced by Aβ25-35.

Alzheimer Disease ; drug therapy ; genetics ; metabolism ; physiopathology ; Amyloid beta-Peptides ; toxicity ; Animals ; Apoptosis ; drug effects ; Cell Survival ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Glucosides ; pharmacology ; Humans ; Monoterpenes ; pharmacology ; Neurons ; cytology ; drug effects ; metabolism ; Neuroprotective Agents ; pharmacology ; PC12 Cells ; Peptide Fragments ; toxicity ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; genetics ; metabolism ; Rats ; Signal Transduction ; drug effects

UNLABELLEDOBJECTIVE To study the in vitro effect and mechanism of Ginkgo biloba Extract 50 (GBE50) for inhibiting beta-amyloid (Abeta)-induced oxidative stress in rats' hippocampal neurons.

METHODSThe primary hippocampal neurons were cultured in vitro and divided into 4 groups, i. e. the normal control group (Ctrl), the Abeta group, the propanediol control group (PDO), and the six GBE50 concentrations groups (5, 10, 25, 50, 100, and 200 microg/mL). Excepted the Ctrl group, neurons were induced to oxidative stress by 20 gmolLAbeta25-35. The MTT and fluorescent probes labeling were used to observe the effect of GBE50 with different concentrations on the cell viability and the generation of intracellular reactive oxygen species (ROS) in neurons. Furthermore, Western blot was used to detect the cytoplasmic/total cytochrome C (Cyto C) ratio and total intracytoplasmal Cyto C, and the effect of the expression of oxidative stress-related protein Cyto C and activated Caspase-3 in three GBE50 concentrations groups (25, 50, and 100 microg/mL).

RESULTSCompared with the Ctrl group, the cell vitality was obviously lowered and intracellular ROS generation significantly increased after induction of 20 micromol/L Abeta25-35 (both P < 0.05). Compared with the Abeta group, the cell vitality was evidently improved after treated with different GBE50 doses. Except for 10 microg/mL, the cell vitality could be obviously elevated along with increased drug concentrations (P < 0.05). Meanwhile, the intracellular ROS generation decreased significantly in each GBE50 dose groups (P < 0.05). Abeta could increase the cytoplasmic/total Cyto C ratio and enhance the activated Caspase-3 expression significantly (P < 0.05). Compared with the Abeta group, among the three concentrations of GBE50, the Cyto C ratio was obviously lowered in the 100 microg/mL GBE50 group (P < 0.05), and the expression of activated Caspase-3 significantly decreased in 50 microg/mL and 100 microg/mL GBE50 groups (P < 0.05).

CONCLUSIONS20 micromol/L Abeta25-35 could induce the generation of intracellular ROS in hippocampal neurons. GBE50 could inhibit Abeta induced intracellular oxidative stress of neurons through lowering the cytoplasmic/total Cyto C ratio and inhibiting the activation of apoptosis protein Caspase-3 expression.

Amyloid beta-Peptides ; toxicity ; Animals ; Cells, Cultured ; Cytochromes c ; metabolism ; Hippocampus ; metabolism ; Neurons ; drug effects ; metabolism ; Oxidative Stress ; drug effects ; Peptide Fragments ; toxicity ; Plant Extracts ; pharmacology ; Rats ; Rats, Sprague-Dawley

BACKGROUNDThe advent of brain stimulation techniques to treat movement disorders and psychiatric diseases has shown potential to decode the neural mechanism that underlies the cognitive process by modulating the interrupted circuit. Here, the present investigation aimed at evaluating the influence of deep brain stimulation of the anterior nucleus thalamus (ANT-DBS) on memory.

METHODSThirty-two rats were randomized into phosphate buffer saline (PBS) group (n = 8, rats received PBS injections without implantation of electrodes into the ANT), Alzheimer's dementia (AD) group (n = 8, rats received A&beta;1-40 injections without implantation of electrodes into the ANT), ANT sham stimulation group (n = 8, rats received A&beta;1-40 injections with implantation of electrodes into the ANT but without stimulation) and ANT stimulation group (n = 8, rats received A&beta;1-40 injections with implantation of electrodes into the ANT and stimulation). A Morris maze test was used for determining the effect of electrical stimulation on cognitive function in rats. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.

RESULTSThe data showed that in the training test, PBS group and AD group managed to learn the hidden-platform faster and faster while AD group needed a significantly longer time to reach the platform than PBS group (P < 0.05). Meanwhile, ANT stimulation group demonstrated a significantly shorter time to reach the platform (P < 0.05) compared to the AD group, while there was no significant difference between the ANT sham stimulation group and the AD group (P > 0.05). On the probe test, the AD group spent less time ((10.15 ± 2.34) seconds) in the target quadrant than the PBS group ((28.20 ± 2.75) seconds) (P < 0.05). And the times of platform-traversing of the AD group (3.35 ± 1.12) significantly decreased compared with the PBS group (8.69 ± 2.87) (P < 0.05). However, the times of platform-traversing and the time spent in the target quadrant of the ANT stimulation group significantly increased compared to the AD group (P < 0.05), while times of platform-traversing or the time spent in the target quadrant was not significantly different between the ANT sham stimulation group and the AD group (P > 0.05).

CONCLUSIONBilateral high-frequency stimulation of the ANT may be useful as a potential therapeutic modality for cognitive dysfunction in AD.

Amyloid beta-Peptides ; administration & dosage ; toxicity ; Animals ; Anterior Thalamic Nuclei ; drug effects ; Cognition ; drug effects ; Cognition Disorders ; chemically induced ; therapy ; Deep Brain Stimulation ; methods ; Hippocampus ; drug effects ; Male ; Peptide Fragments ; administration & dosage ; toxicity ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effect of berberine on expressions of tumor necrosis factor alpha (TNF-alpha) and receptor type I (TNFR1) in Abeta25-35-induced inflammatory reaction in SH-SYSY cell lines.

METHODThe 5 micromol . L-1 Abeta25-35 was used to treat SH-SY5Y cells for 24 hours, in order to establish the Alzheimer's disease (AD) model. Before modeling, berberine was given for pretreatment for 2 hours. The experiment included the normal control group, the AD model group, and indometacin low dose and high dose groups. Spectrophotometry was adopted to detect the activity of LDH. Meanwhile, the level of TNF-alpha was determined by ELISA, and the expression of TNFR1 genes was detected by RT-PCR.

RESULTCompared with the normal control group, the AD cell model group showed significant increase in LDH, TNF-alpha, and TNFR1 gene and protein expressions in the culture media. After intervention with berberine, the activity of LDH and TNF-alpha reduced in cell supernatant. The intervention with berberine could down-regulate TNFR1 gene and protein expressions, particularly 1, 10 x 10(-6) mol . L-l berberine showed a more notable effect in regulating TNFR1.

CONCLUSIONBerberine has the protective effect in Abeta-induced inflammatory injury in SH-SY5Y cells. Its mechanism may be related to the expression of its anti inflammatory factor TNF-alpha and its type I receptor TNFR1. Specifically, its regulation to TNFR1 shows dose dependence.

Amyloid beta-Peptides ; toxicity ; Berberine ; pharmacology ; Cell Line ; Humans ; Inflammation ; chemically induced ; metabolism ; Peptide Fragments ; toxicity ; Receptors, Interleukin-1 Type I ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism