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Wang J.,Hebei Medical University | Yuan J.,University of Science and Technology of China | Pang J.,University of Science and Technology of China | Ma J.,First Hospital of Shijiazhuang | And 8 more authors.
Cellular Physiology and Biochemistry | Year: 2016

Background/Aims: Chronic stress can lead to cognitive impairment. Senescence-accelerated mouse prone 8 (SAMP8) is a naturally occurring animal model that is useful for investigating the neurological mechanisms of Alzheimer's disease. Here we investigated the impact and mechanisms of chronic stress on cognition in male SAMP8 mice. Methods: Male 6-month- old SAMP8 and SAMR1 (senescence-accelerated mouse resistant 1) mice strains were randomly divided into 4 groups. Mice in the unpredictable chronic mild stress (UCMS) groups were exposed to diverse stressors for 4 weeks. Then, these mice performed Morris water maze (MWM) test to assess the effect of UCMS on learning and memory. To explore the neurological mechanisms of UCMS on cognition in mice, we evaluated changes in the expression of postsynaptic density 95 (PSD95) and synaptophysin (SYN), which are essential proteins for synaptic plasticity. Five mice from each group were randomly chosen for reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis of SYN and PSD95. Results: The Morris water maze experiment revealed that the cognitive ability of the SAMP8 mice decreased with brain aging, and that chronic stress aggravated this cognitive deficit. In addition, chronic stress decreased the mRNA and protein expression of SYN and PSD95 in the hippocampus of the SAMP8 mice; however, the SAMR1 mice were unaffected. Conclusion: Our results demonstrate that decreased cognition and synaptic plasticity are related to aging. Moreover, we show that chronic stress aggravated this cognitive deficit and decreased SYN and PSD95 expression in the SAMP8 mice. Furthermore, the SAMP8 mice were more vulnerable to the detrimental effects of chronic stress on cognition than the SAMR1 mice. Our results suggest that the neurological mechanisms of chronic stress on cognition might be associated with a decrease in hippocampal SYN and PSD95 expression, which is critical for structural synaptic plasticity. © 2016 The Author(s) Published by S. Karger AG, Basel.


Wang H.-L.,Hebei Medical University | Wang Y.-Y.,Hebei Medical University | Liu X.-G.,Jingxing Hospital | Kuo S.-H.,Columbia University | And 4 more authors.
Journal of Alzheimer's Disease | Year: 2016

Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: Aβ42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as Aβ42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD. © 2016 - IOS Press and the authors. All rights reserved.


Wang H.,Hebei Medical University | Lian K.,Hebei Medical University | Han B.,Hebei Medical University | Wang Y.,Hebei Medical University | And 6 more authors.
Journal of Alzheimer's Disease | Year: 2014

Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder, produces a progressive decline in cognitive function. The metabolic mechanism of AD has emerged in recent years. In this study, we used multivariate analyses of gas chromatography-mass spectrometry measurements to determine that learning and retention-related metabolic profiles are altered during aging in the hippocampus of the senescence-accelerated mouse prone 8 (SAMP8). Alterations in 17 metabolites were detected in mature and aged mice compared to young mice (13 decreased and 4 increased metabolites), including metabolites related to dysfunctional lipid metabolism (significantly increased cholesterol, oleic acid, and phosphoglyceride levels), decreased amino acid (alanine, serine, glycine, aspartic acid, glutamate, and gamma-aminobutyric acid), and energy-related metabolite levels (malic acid, butanedioic acid, fumaric acid, and citric acid), and other altered metabolites (increased N-acetyl-aspartic acid and decreased pyroglutamic acid, urea, and lactic acid) in the hippocampus. All of these alterations indicated that the metabolic mechanisms of age-related cognitive impairment in SAMP8 mice were related to multiple pathways and networks. Lipid metabolism, especially cholesterol metabolism, appears to play a distinct role in the hippocampus in AD. © 2014-IOS Press and the authors. All rights reserved.


Xu S.,Hebei Medical University | Xu S.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province | Xie B.,Hebei Medical University | Xie B.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province | And 14 more authors.
Neuroepidemiology | Year: 2014

Background: Mild cognitive impairment (MCI) has been suggested as a term for a boundary area between normal aging and dementia. This study was designed to determine the prevalence of MCI in the elderly in the Hebei province, China, and explore its related factors. Methods: Participants included 2,601 community-dwelling people aged 60 years or older who resided in the four major cities of the Hebei province. In stage 1 of the study, the Mini-Mental State Examination and the Montreal Cognitive Assessment were administered for screening purposes. In stage 2, the subjects who screened positive were further examined by neurologists. The diagnosis of MCI was made according to Petersen's criteria. Results: The estimated prevalence of MCI was 21.3%. MCI was more prevalent at age 65-69 (28.3%), and its overall rates among men (24.1%) were higher than those of women (19.9%). The higher prevalence of MCI was associated with very old age (≥80 years old; OR = 2.457, 95% CI = 1.471-4.104), male gender (OR = 1.363, 95% CI = 1.097-1.694), low education level (OR = 2.439, 95% CI = 1.623-3.663), and poor economic status (OR = 2.882, 95% CI = 1.949-4.255). Conclusions: Our findings show a high prevalence of MCI in the elderly urban population in the Hebei province. Gender, education level, and economic status may have an important role in the etiology of MCI. © 2014 S. Karger AG, Basel.


Han B.,Hebei Medical University | Yu L.,Hebei Medical University | Geng Y.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province | Shen L.,Hebei Medical University | And 5 more authors.
Journal of Alzheimer's Disease | Year: 2016

Differences in brain function are a central determinant of individual variability in the stress response. Brain dysfunction, resulting from aging, illness, or genetic mutations, could reduce the tolerance of glucocorticoid stress hormones. When glucocorticoids exceed tolerable limits in the brain, especially in the hippocampus, this state can cause or aggravate structural or functional damage. However, the underlying mechanisms are not well understood. This study investigated the effects of chronic unpredictable mild stress (CUMS) in APP/PS1 and control mice. We showed that 4 weeks of CUMS exposure increased the levels of glucocorticoids, reduced glucocorticoids receptor expression, and promoted senile plaque deposition, neuronal injury, and cognitive impairment in APP/PS1 mice compared to controls. The phosphorylation of insulin receptor, insulin receptor substrate 1 and associated signaling pathways (Akt, mTOR, p70S6K, ERK1/2, and PTEN) were decreased in hippocampus in APP/PS1 mice compared to control mice, while no changes were found in GSK3 and TSC2 phosphorylation. Furthermore, insulin and Akt/mTOR signaling pathways were further decreased in APP/PS1 mice after CUMS, which may be related to the activation of the stress-activated protein kinase JNK, while no alterations in the levels of phosphorylated ERK1/2, GSK3, PTEN, or TSC2 were observed. These results suggest that chronic stress may affect the insulin and Akt/mTOR pathway, accelerating the progression of Alzheimer's disease in vulnerable individuals.


Wang H.,Hebei Medical University | Geng Y.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province | Han B.,Hebei Medical University | Qiang J.,Hebei Medical University | And 5 more authors.
PLoS ONE | Year: 2013

Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that has recently received increasing interests as a therapeutic procedure for neurodegenerative diseases. To identify the metabolism mechanism underlying the improving effects of rTMS, we observed that high frequency (25Hz) rTMS for 14 days could reverse the decline of the performance of the passive avoidance task in aged mice. We further investigated the metabolite profiles in the prefrontal cortex (PFC) in those mice and found that rTMS could also reverse the metabolic abnormalities of gamma-aminobutyric acid, N-acetyl aspartic, and cholesterol levels to the degree similar to the young mice. These data suggested that the rTMS could ameliorate the age-related cognitive impairment and improving the metabolic profiles in PFC, and potentially can be used to improve cognitive decline in the elderly. © 2013 Wang et al.


Ma Q.,Hebei Medical University | Ma Q.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei province | Qiang J.,Hebei Medical University | Qiang J.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei province | And 8 more authors.
Experimental Gerontology | Year: 2011

Autophagy is responsible for the degradation of long-lived proteins and damaged organelles intracellular, even extracellular,and autophagy is proved to have relationship with Alzheimer's disease (AD) and aging. The senescence accelerated mouse prone 8 (SAMP8) was a non-genetically modified mice widely used as a rodent model of aging and senile dementia. However, little was known about the age-related changes of autophagy in the brain of SAMP8 mice. To better understand the precise relationship between aging, autophagy and neurodegeneration, we explored the time course of cognitive ability, ubiquitin-positive inclusions, ultrastructure of neurons and detected the expression of LC3 and Beclin 1 protein in different brain regions of 2, 7 and 12-month-old SAMP8 and SAMR1 mice. We found that 7 and 12-month-old SAMP8 mice presented cognitive decline and ubiquitinated proteins enhanced. In the hippocampal neurons of 12-month-old SAMP8 mice, lots of dense clumps and autophagic vacuoles were found in the cytoplasm and axons. The LC3-II expression showed an increase in hippocampus and cortex of 7 and 12-month-old SAMP8 mice. The expression of Beclin 1 displayed a significant increase in 7. months old and a decline in 12. months old mice. Based on these data, we suggest that the autophagic activity maybe increase reactively at the beginning of AD and then showed a decline with aging, and the pathological changes of 12-month-old SAMP8 mice are more similar to the late-onset AD in the perspective of autophagy. © 2011.


Wang H.-L.,Hebei Medical University | Xian X.-H.,Hebei Medical University | Wang Y.-Y.,Hebei Medical University | Geng Y.,Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province | And 5 more authors.
Neurobiology of Learning and Memory | Year: 2015

Chronic high-frequency repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to increase the excitability of neurons, and it induces long-term effects that can improve symptoms related to neurodegenerative diseases, including cognitive ability. The present study was undertaken to identify the mechanism by which rTMS improves cognitive impairments in mice. The novel object recognition test in vivo was used to evaluate the cognitive function of the mice. Whole-cell patch-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials induced by depolarized current, after-hyperpolarization, and the voltage-dependent Ca2+ current in hippocampal slices. We found that the aged mice showed impairments in cognitive function, and high-frequency (25Hz) rTMS for 14 consecutive-days ameliorated the impairments. Whole-cell patch-clamp recordings showed that, compared to matured mice, the hippocampal CA1 pyramidal neurons of aged mice showed significantly hyperpolarized resting membrane potential, significantly decreased numbers of action potentials after injection of depolarizing current, and significantly increased after-hyperpolarization after an action potential. The exposure to high-frequency rTMS significantly improved the above deficits in the neuronal excitability in the aged rTMS mice. Consistent with the above changes, the exposure to high-frequency rTMS also significantly decreased the voltage-dependent Ca2+ current of the neurons compared with the aged sham mice. These data suggested that the rTMS could improve the age-related cognitive impairment in parallel with regulating the neuronal excitability and modifying the voltage-dependent Ca2+ channels. © 2014 Elsevier Inc.


PubMed | Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Hebei Medical University and Columbia University
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2014

Alzheimers disease (AD), the most common age-dependent neurodegenerative disorder, produces a progressive decline in cognitive function. The metabolic mechanism of AD has emerged in recent years. In this study, we used multivariate analyses of gas chromatography-mass spectrometry measurements to determine that learning and retention-related metabolic profiles are altered during aging in the hippocampus of the senescence-accelerated mouse prone 8 (SAMP8). Alterations in 17 metabolites were detected in mature and aged mice compared to young mice (13 decreased and 4 increased metabolites), including metabolites related to dysfunctional lipid metabolism (significantly increased cholesterol, oleic acid, and phosphoglyceride levels), decreased amino acid (alanine, serine, glycine, aspartic acid, glutamate, and gamma-aminobutyric acid), and energy-related metabolite levels (malic acid, butanedioic acid, fumaric acid, and citric acid), and other altered metabolites (increased N-acetyl-aspartic acid and decreased pyroglutamic acid, urea, and lactic acid) in the hippocampus. All of these alterations indicated that the metabolic mechanisms of age-related cognitive impairment in SAMP8 mice were related to multiple pathways and networks. Lipid metabolism, especially cholesterol metabolism, appears to play a distinct role in the hippocampus in AD.


PubMed | Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province and Hebei Medical University
Type: Journal Article | Journal: Neural regeneration research | Year: 2015

In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinsons disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5-bromo-2-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinsons disease. Immunohistochemical staining showed that, 5-bromo-2-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinsons disease.

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