The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuro...The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuropathology,but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown.Here,we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy.Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1βproduction in microglia.Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury.Importantly,we showed that chronic administration of MCC950,a novel selective NLRP3 inhibitor,to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function.In conclusion,our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.展开更多
Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.Howeve...Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.展开更多
2008113 Experimental study of the apoptosis in rat hippocampus induced by high iodine. YUE Dan(岳丹), et al. Dept Biochem, Liaoning Med Coll, Jinzhou 121001. Chin J Endemiol 2007;26(6):611-615. Objective To investi...2008113 Experimental study of the apoptosis in rat hippocampus induced by high iodine. YUE Dan(岳丹), et al. Dept Biochem, Liaoning Med Coll, Jinzhou 121001. Chin J Endemiol 2007;26(6):611-615. Objective To investigate the morphological structure and the mechanism of the apoptosis in rat hippocampus induced by high iodine. Methods An animal model of goiter was reconstructed in rat fed with water containing high level of iodine展开更多
We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neuro...We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.展开更多
Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular me...Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.展开更多
In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) co...In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) contain proteins,RNAs and lipids,and their internalization by bystander cells could alter their normal functions.This review focuses on recent knowledge about exosomes as messengers of neuron-glia communication and their participation in the physiological and pathological functions in the central nervous system.Special emphasis is placed on the role of exosomes under toxic or pathological stimuli within the brain,in which the glial exosomes containing inflammatory molecules are able to communicate with neurons and contribute to the pathogenesis of neuroinflammation and neurodegenerative disorders.Given the small size and characteristics of exosomes,they can cross the blood-brain barrier and be used as biomarkers and diagnosis for brain disorders and neuropathologies.Finally,although the application potential of exosome is still limited,current studies indicate that exosomes represent a promising strategy to gain pathogenic information to identify therapeutically targets and biomarkers for neurological disorders and neuroinflammation.展开更多
The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intr...The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.展开更多
Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that mefloquine may be ototoxic and neurotoxic, but there is little scientific evidence from which to draw any firm conclusion. To evaluate...Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that mefloquine may be ototoxic and neurotoxic, but there is little scientific evidence from which to draw any firm conclusion. To evaluate the ototoxic and neurotoxic potential of mefloquine, we treated cochlear organotypic cultures and spiral ganglion cultures with various concentrations of mefloquine. Mefloquine caused a dose-dependent loss of cochlear hair cells at doses exceeding 0.01 mM. Hair cell loss progressed from base to apex and from outer to inner hair cells with increasing dose. Spiral ganglion neurons and auditory nerve fibers were also rapidly destroyed by mefloquine in a dose-dependent manner. To investigate the mechanisms underlying mefloquine-induced cell death, cochlear cultures were stained with TO-Pro-3 to identify morphological changes in the nucleus, and with carboxyfluorescein FAM-labeled caspase inhibitor 8, 9 or 3 to determine caspase-mediated cell death. TO-Pro-3-labeled nuclei in hair cells, spiral ganglion neurons and supporting cells were shrunken or fragmented, morphological features characteristic of cells undergoing apoptosis. Both initiator caspase 8 (membrane damage) and caspase 9 (mitochondrial damage), along with executioner caspase 3, were heavily expressed in cochlear hair cells and spiral ganglions after mefloquine treatment. These three caspases were also expressed in support cells, although labeling was less widespread and less intense. These results indicate that mefloquine damages both the sensory and neural elements in the postnatal rat cochlea by initially activating cell death signaling pathways on the cell membrane and in mitochondria.展开更多
The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenu...The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenual region in bipolar disorder and depression, with overall glial number shown to be decreased in these disorders. Decreases in subgenual grey matter in SZ have been observed also. In this neuropathological study upon formalin-fixed coronal brain sections we describe the morphological finding of de- creased frequency of subgenual cingulate crown bifurcation (p = 0.02) as compared to control, bipolar and depression cases. This suggests that the cingulate cortex in schizophrenia may be morphologically distinct in utero formation, potentially enabling an early identification of high-risk individuals.展开更多
Neglected tropical diseases are a group of tropical diseases endemic in poor countries even though medical treatment and cures are available. They are considered a global health problem due to the severity of the phys...Neglected tropical diseases are a group of tropical diseases endemic in poor countries even though medical treatment and cures are available. They are considered a global health problem due to the severity of the physiological changes they induce in their hosts. Malaria is a disease caused by Plasmodium sp. that in its cerebral form may lead to acute or long-term neurological deficits, even with effective antimalarial therapy, causing vascular obstruction, reduced cerebral blood flow and many other changes. However, Plasmodium falciparum infection can also develop into a cerebral malaria(CM) disease that can produce neurological damage. This review will discuss the mechanisms involved in the neuropathology caused by CM, focusing on alterations in cognitive, behavior and neurological functions in human and experimental models.展开更多
Maintenance with methadone is standard treatment for opioid-addicted patients, including pregnant women. Cellular effects of methadone exposure during development are investigated by using an avian model, which is fre...Maintenance with methadone is standard treatment for opioid-addicted patients, including pregnant women. Cellular effects of methadone exposure during development are investigated by using an avian model, which is free of confounding maternal variables. In the first study, which explored dose by duration interactions, methadone was administered at one of two doses (0.458 mg/kg or 1.75 mg/kg) for one of three durations of exposure: late in development (Incubation Days 12 to 19), middle to late (Days 9 to 19), or early to late (Days 5 to 19). In the second study, 1.00 mg/kg of methadone was administered from days 8 to 18 and compared with controls (0.00 mg/kg). Brain tissue and blood samples were harvested for all dose conditions from the two studies. Increased methadone exposure was associated with subependymal anomalies, subependymal hemorrhaging, edema, monocytic infiltration, an increase in disintegrating red blood cells, an increase in white blood cells, and a decrease in neurons. Significant differences in variance for cell counts by condition were observed. Exposed specimens had significantly more thrombocytes (t = - 2.66, p < 0.05). The anomalies suggest that methadone exposure may be harmful to develop organisms at the cellular level.展开更多
Mavridis' atrophy(MA) is called the human nucleus accumbens(NA) atrophy in Parkinson's disease(PD).MA begins in early-stage PD patients and is correlated with psychiatric symptoms that occur in PD, mainly apat...Mavridis' atrophy(MA) is called the human nucleus accumbens(NA) atrophy in Parkinson's disease(PD).MA begins in early-stage PD patients and is correlated with psychiatric symptoms that occur in PD, mainly apathy and impulsive behavior. It is also associated with cognitive PD symptoms. Purpose of this editorial was to discuss the future perspectives of MA as apathological and imaging finding. MA is obviously part of the degeneration of the dopaminergic nigrostriatal system that occurs in PD and this also explains the fact that MA precedes clinical phenotype. But does the human NA follow the same pattern of degeneration? It would be quite interesting to have a post-mortem pathological study focused on the NA of parkinsonic individuals. Further questions that remain to be answered are whether all parkinsonics suffer MA and whether this phenomenon is also associated with motor PD symptoms. MA as an imaging finding could be a risk factor for the expression and/or severity of specific PD symptoms. It has therefore to be tested whether the presence of MA is related, for example, with the expression and/or severity of motor PD symptoms and whether the severity of MA affects the severity of specific psychiatric symptoms(apathy, compulsive behavior) of parkinsonic individuals. Such clinical studies, that could provide answers to these vital questions, can be easily preformed given the high frequency of PD in modern populations. Future research efforts are mandatory to enrich our knowledge of MA, namely its underlying mechanisms, its pathological features and its clinical consequences.展开更多
The article aims to underline the impact of nicotine and pesticides on neuronal <i>α</i>7-nicotinic acetylcholine receptors expression in brainstem regions receiving cholinergic projections, given their f...The article aims to underline the impact of nicotine and pesticides on neuronal <i>α</i>7-nicotinic acetylcholine receptors expression in brainstem regions receiving cholinergic projections, given their fundamental role during the neuronal development. The in-depth histopathological/immunohistochemical examination of the autonomic nervous system performed at the “Lino Rossi” Research Center of the Milan University on a wide group of sudden unexpected fetal and infant deaths, highlighted the frequent hypodevelopment of brainstem structures checking the vital functions associated to altered expression of <i>α</i>7-nicotinic acetylcholine receptors and smoke absorption in pregnancy. A dysregulation of the catecholamine system was also observed in the cerebellar cortex of the same cases. However, in a not negligible percentage of sudden deaths with altered expression of <i>α</i>7-nicotinic receptors, the mothers never smoked but lived in rural areas. Specific analytical procedures showed the presence of agricultural pesticides in cerebral cortex samples of these victims. Therefore, it is possible to believe that the exposition to pesticides during pregnancy can produce the same harmful effects as nicotine on the nicotinic acetylcholine receptors. Moreover, alterations of <i>α</i>7-nicotinic acetylcholine receptors receptor expression were also detected in the lungs of many sudden perinatal death victims, allowing to consider even these findings as possible consequence of maternal exposure to toxic factors.展开更多
Introduction: Ventriculomegaly is one of the most common abnormalities detected by prenatal ultrasound. This entity can be associated with brain abnormalities and other malformations. In order to perform a good prenat...Introduction: Ventriculomegaly is one of the most common abnormalities detected by prenatal ultrasound. This entity can be associated with brain abnormalities and other malformations. In order to perform a good prenatal counseling, the diagnosis is essential. Objective: Our purpose was to report the management of 3 cases of ventriculomegaly in our practice and underline the benefits of the neuropathologic exam. Methods: We analyzed retrospectively 3 medical files concerning fetus that were diagnosed as having one or two ventricles of >10 mm and a follow up for prenatal diagnosis. Results: All cases were diagnosed between 22 and 27 weeks of gestation by an ultrasound. In a case, the ventriculomegaly evolved rapidly to a hydrocephalus. In two cases, the pregnancy was terminated with medical interruption by the parent’s request. Amniocentesis confirmed the diagnosis of congenital toxoplasmosis in case 2 there were no chromosomal abnormalities after karyotyping. Causes included holoprosencephaly, congenital toxoplasmosis and mesencephalosynapsis. Conclusion: Ultrasonography may detect ventriculomegaly nerverthless in the cases presented, pathology exam was essential to assess the diagnostic. Causes are numerous and prognosis variable. We recommand MRI that is more and more accessible in our regions in the follow up of this entity and neuropathology exam in case of termination of the pregnancy. The establishment of main causes of ventriculomegaly in our regions (infectious causes for example) could help to prevent this outcome in our practice.展开更多
Hydrocephalus is a heterogeneous, neurological condition characterized by altered flow of cerebrospinal fluid (CSF) that can occur at any age. Neuropathological changes associated with hydrocephalus are dependent on t...Hydrocephalus is a heterogeneous, neurological condition characterized by altered flow of cerebrospinal fluid (CSF) that can occur at any age. Neuropathological changes associated with hydrocephalus are dependent on the age of onset, rate of ventricular enlargement, and the etiology. Hydrocephalic brain damage is also influenced by contributions from both mechanical forces and metabolic changes, which increases the heterogeneity of the condition. However, as ventriculomegaly progresses, the surrounding brain tissue is compressed within the cranial vault, elevating intracranial pressure and eventually leading to severe brain damage. From this perspective, it makes sense that periventricular brain regions are the initial sites of damage as ventricular dilatation occurs. The following review of neuropathological changes in hydrocephalus will first discuss cellular and region specific damage from the ventricles and outward towards the cortex and brainstem. This will be followed by vascular and hypoxic changes associated with the condition. Both types of brain impairments are dependent on the severity of the condition, and they will be described accordingly.展开更多
The fast aging human population requires new approaches to reliable diagnosis and proper treatment of dementia in elderly patients with psychiatric disorders such as bipolar disorder (BD) and schizophrenia (SCZ). As c...The fast aging human population requires new approaches to reliable diagnosis and proper treatment of dementia in elderly patients with psychiatric disorders such as bipolar disorder (BD) and schizophrenia (SCZ). As compared to other psychiatric disorders, BD and SCZ are characterized by increased and similar risk for dementia as well as cerebrovascular (CVD) and Parkinson’s (PD) diseases independent of the patient’s age. There are reports in the literature suggesting BD and SCZ in older patients could cause dementia without contribution from the neurodegenerative diseases, including Alzheimer’s disease (AD), due to the absence of the known neuropathology associated with cognitive decline in such individuals. This view contradicts a plethora of data highlighting AD as a major cause of dementia in the elderly. This issue was addressed by examining postmortem cerebral pathology in an 83-year-old female diagnosed with BD, SCZ, and PD (D1) and comparing it to that of a second donor (D2), an age-matched male diagnosed with Lewy Body Dementia (LBD). Upon thorough histochemical and immunohistochemical examinations of both brains, the PD and LBD diagnoses in D1 and D2 were not confirmed. Instead, AD-related pathology was observed in both subjects with AD advancing to its clinical stage (mild to moderate) only in D1. Diffuse β-amyloid peptide 1-42 (Aβ1-42) staining, most likely reflecting a presence of the Aβ1-42 soluble form, was also detected in cerebellar neurons and cerebellar extracellular space in D1 and D2. Cerebrovascular pathology was pronounced and distinct in both brains and included amyloid angiopathy, hyaline atherosclerosis, microbleeds, and dilated Virchow Robin spaces in D1 as well as thick-walled blood vessels with microbleeds in D2. It was concluded that a mixed AD and cerebrovascular pathology could mimic Lewy Body Disease and potentially contribute to dementia development in elderly BD and SCZ patients.展开更多
Gut dysbiosis,a well-known risk factor to triggers the progression of Alzheimer's disease(AD),is strongly associated with metabolic disturbance.Trimethylamine N-oxide(TMAO),produced in the dietary choline metaboli...Gut dysbiosis,a well-known risk factor to triggers the progression of Alzheimer's disease(AD),is strongly associated with metabolic disturbance.Trimethylamine N-oxide(TMAO),produced in the dietary choline metabolism,has been found to accelerate neurodegeneration in AD pathology.In this study,the cognitive function and gut microbiota of TgCRND8(Tg)mice of different ages were evaluated by Morris water maze task(MWMT)and 16S rRNA sequencing,respectively.Young pseudo germ-free(PGF)Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type(WT)mice were selected to determine the role of the gut microbiota in the process of neuropathology.Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions.Our results showed that gut dysbiosis,neuroinflammation response,Ab deposition,tau hyperphosphorylation,TMAO overproduction and cyclin-dependent kinase 5(CDK5)/transcription 3(STAT3)activation occurred in Tg mice age-dependently.Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice,with the activation of CDK5/STAT3 signaling in the brains.On the contrary,faecal microbiota transplantation from WT mice alleviated the cognitive deficits,attenuated neuroinflammation,Ab deposition,tau hyperphosphorylation,TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice.Moreover,excessive choline treatment was also shown to aggravate the cognitive deficits,Ab deposition,neuroinflammation and CDK5/STAT3 pathway activation.These findings provide a novel insight into the interaction between gut dysbiosis and AD progression,clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.展开更多
Background:Individuals with subjective memory complaints(SMC)feature a higher risk of cognitive decline and clinical progression of Alzheimer’s disease(AD).However,the pathological mechanism underlying SMC remains un...Background:Individuals with subjective memory complaints(SMC)feature a higher risk of cognitive decline and clinical progression of Alzheimer’s disease(AD).However,the pathological mechanism underlying SMC remains unclear.We aimed to assess the intrinsic connectivity network and its relationship with AD-related pathologies in SMC individuals.Methods:We included 44 SMC individuals and 40 normal controls who underwent both resting-state functional MRI and positron emission tomography(PET).Based on graph theory approaches,we detected local and global functional connectivity across the whole brain by using degree centrality(DC)and eigenvector centrality(EC)respectively.Additionally,we analyzed amyloid deposition and tauopathy via florbetapir-PET imaging and cerebrospinal fluid(CSF)data.The voxel-wise two-sample T-test analysis was used to examine between-group differences in the intrinsic functional network and cerebral amyloid deposition.Then,we correlated these network metrics with pathological results.Results:The SMC individuals showed higher DC in the bilateral hippocampus(HP)and left fusiform gyrus and lower DC in the inferior parietal region than controls.Across all subjects,the DC of the bilateral HP and left fusiform gyrus was positively associated with total tau and phosphorylated tau181.However,no significant between-group difference existed in EC and cerebral amyloid deposition.Conclusion:We found impaired local,but not global,intrinsic connectivity networks in SMC individuals.Given the relationships between DC value and tau level,we hypothesized that functional changes in SMC individuals might relate to pathological biomarkers.展开更多
Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that w...Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA(miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex(BA 46)(n = 74 matched pairs of schizophrenia, schizoaffective, and control samples)was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92 a, miR-495,and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11 A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that mi RNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.展开更多
基金This project was financially supported by the Key Program of the Natural Science Foundation of Guangdong,China(No.2017B030311017)the National Natural Science Foundation of China(No.81370740)+1 种基金the Program of the Natural Science Foundation of Guangdong,China(No.2018A030313845)the China Postdoctoral Science Foundation(No.2018M633076).
文摘The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuropathology,but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown.Here,we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy.Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1βproduction in microglia.Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury.Importantly,we showed that chronic administration of MCC950,a novel selective NLRP3 inhibitor,to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function.In conclusion,our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.
基金This work was supported by grants Beijing Natural Science Foundation(No.517100)National Key Research and Development Project(No.2017YFA0105200)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-2-006).
文摘Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.
文摘2008113 Experimental study of the apoptosis in rat hippocampus induced by high iodine. YUE Dan(岳丹), et al. Dept Biochem, Liaoning Med Coll, Jinzhou 121001. Chin J Endemiol 2007;26(6):611-615. Objective To investigate the morphological structure and the mechanism of the apoptosis in rat hippocampus induced by high iodine. Methods An animal model of goiter was reconstructed in rat fed with water containing high level of iodine
基金supported by grants from the New Jersey Commission on Spinal Cord Research (05-304711-015)
文摘We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.
基金supported by the National Natural Science Foundation of China, No. 81771140 (to YDZ)the Natural Science Foundation of Jiangsu Province of China, No. BK20201117 (to YDZ)Jiangsu “Six One Project” for Distinguished Medical Scholars of China, No. LGY2020013 (to TJ)
文摘Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.
基金supported by grants from the Health Ministry,PNSD(2018-I003)Institute Carlos III and FEDER funds(RTA-Network,RD16 0017 0004)+1 种基金Spanish Ministry of Science and Innovation(SAF2015-69187R)FEDER Funds,Generalitat Valenciana
文摘In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) contain proteins,RNAs and lipids,and their internalization by bystander cells could alter their normal functions.This review focuses on recent knowledge about exosomes as messengers of neuron-glia communication and their participation in the physiological and pathological functions in the central nervous system.Special emphasis is placed on the role of exosomes under toxic or pathological stimuli within the brain,in which the glial exosomes containing inflammatory molecules are able to communicate with neurons and contribute to the pathogenesis of neuroinflammation and neurodegenerative disorders.Given the small size and characteristics of exosomes,they can cross the blood-brain barrier and be used as biomarkers and diagnosis for brain disorders and neuropathologies.Finally,although the application potential of exosome is still limited,current studies indicate that exosomes represent a promising strategy to gain pathogenic information to identify therapeutically targets and biomarkers for neurological disorders and neuroinflammation.
文摘The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.
文摘Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that mefloquine may be ototoxic and neurotoxic, but there is little scientific evidence from which to draw any firm conclusion. To evaluate the ototoxic and neurotoxic potential of mefloquine, we treated cochlear organotypic cultures and spiral ganglion cultures with various concentrations of mefloquine. Mefloquine caused a dose-dependent loss of cochlear hair cells at doses exceeding 0.01 mM. Hair cell loss progressed from base to apex and from outer to inner hair cells with increasing dose. Spiral ganglion neurons and auditory nerve fibers were also rapidly destroyed by mefloquine in a dose-dependent manner. To investigate the mechanisms underlying mefloquine-induced cell death, cochlear cultures were stained with TO-Pro-3 to identify morphological changes in the nucleus, and with carboxyfluorescein FAM-labeled caspase inhibitor 8, 9 or 3 to determine caspase-mediated cell death. TO-Pro-3-labeled nuclei in hair cells, spiral ganglion neurons and supporting cells were shrunken or fragmented, morphological features characteristic of cells undergoing apoptosis. Both initiator caspase 8 (membrane damage) and caspase 9 (mitochondrial damage), along with executioner caspase 3, were heavily expressed in cochlear hair cells and spiral ganglions after mefloquine treatment. These three caspases were also expressed in support cells, although labeling was less widespread and less intense. These results indicate that mefloquine damages both the sensory and neural elements in the postnatal rat cochlea by initially activating cell death signaling pathways on the cell membrane and in mitochondria.
文摘The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenual region in bipolar disorder and depression, with overall glial number shown to be decreased in these disorders. Decreases in subgenual grey matter in SZ have been observed also. In this neuropathological study upon formalin-fixed coronal brain sections we describe the morphological finding of de- creased frequency of subgenual cingulate crown bifurcation (p = 0.02) as compared to control, bipolar and depression cases. This suggests that the cingulate cortex in schizophrenia may be morphologically distinct in utero formation, potentially enabling an early identification of high-risk individuals.
基金Conselho Nacional de Desenvolvi-mento Científico e Tecnológico (CNPq), FAPESPA, Federal University of Pará and the Federal University of Health Sciences of Porto Alegre
文摘Neglected tropical diseases are a group of tropical diseases endemic in poor countries even though medical treatment and cures are available. They are considered a global health problem due to the severity of the physiological changes they induce in their hosts. Malaria is a disease caused by Plasmodium sp. that in its cerebral form may lead to acute or long-term neurological deficits, even with effective antimalarial therapy, causing vascular obstruction, reduced cerebral blood flow and many other changes. However, Plasmodium falciparum infection can also develop into a cerebral malaria(CM) disease that can produce neurological damage. This review will discuss the mechanisms involved in the neuropathology caused by CM, focusing on alterations in cognitive, behavior and neurological functions in human and experimental models.
文摘Maintenance with methadone is standard treatment for opioid-addicted patients, including pregnant women. Cellular effects of methadone exposure during development are investigated by using an avian model, which is free of confounding maternal variables. In the first study, which explored dose by duration interactions, methadone was administered at one of two doses (0.458 mg/kg or 1.75 mg/kg) for one of three durations of exposure: late in development (Incubation Days 12 to 19), middle to late (Days 9 to 19), or early to late (Days 5 to 19). In the second study, 1.00 mg/kg of methadone was administered from days 8 to 18 and compared with controls (0.00 mg/kg). Brain tissue and blood samples were harvested for all dose conditions from the two studies. Increased methadone exposure was associated with subependymal anomalies, subependymal hemorrhaging, edema, monocytic infiltration, an increase in disintegrating red blood cells, an increase in white blood cells, and a decrease in neurons. Significant differences in variance for cell counts by condition were observed. Exposed specimens had significantly more thrombocytes (t = - 2.66, p < 0.05). The anomalies suggest that methadone exposure may be harmful to develop organisms at the cellular level.
文摘Mavridis' atrophy(MA) is called the human nucleus accumbens(NA) atrophy in Parkinson's disease(PD).MA begins in early-stage PD patients and is correlated with psychiatric symptoms that occur in PD, mainly apathy and impulsive behavior. It is also associated with cognitive PD symptoms. Purpose of this editorial was to discuss the future perspectives of MA as apathological and imaging finding. MA is obviously part of the degeneration of the dopaminergic nigrostriatal system that occurs in PD and this also explains the fact that MA precedes clinical phenotype. But does the human NA follow the same pattern of degeneration? It would be quite interesting to have a post-mortem pathological study focused on the NA of parkinsonic individuals. Further questions that remain to be answered are whether all parkinsonics suffer MA and whether this phenomenon is also associated with motor PD symptoms. MA as an imaging finding could be a risk factor for the expression and/or severity of specific PD symptoms. It has therefore to be tested whether the presence of MA is related, for example, with the expression and/or severity of motor PD symptoms and whether the severity of MA affects the severity of specific psychiatric symptoms(apathy, compulsive behavior) of parkinsonic individuals. Such clinical studies, that could provide answers to these vital questions, can be easily preformed given the high frequency of PD in modern populations. Future research efforts are mandatory to enrich our knowledge of MA, namely its underlying mechanisms, its pathological features and its clinical consequences.
文摘The article aims to underline the impact of nicotine and pesticides on neuronal <i>α</i>7-nicotinic acetylcholine receptors expression in brainstem regions receiving cholinergic projections, given their fundamental role during the neuronal development. The in-depth histopathological/immunohistochemical examination of the autonomic nervous system performed at the “Lino Rossi” Research Center of the Milan University on a wide group of sudden unexpected fetal and infant deaths, highlighted the frequent hypodevelopment of brainstem structures checking the vital functions associated to altered expression of <i>α</i>7-nicotinic acetylcholine receptors and smoke absorption in pregnancy. A dysregulation of the catecholamine system was also observed in the cerebellar cortex of the same cases. However, in a not negligible percentage of sudden deaths with altered expression of <i>α</i>7-nicotinic receptors, the mothers never smoked but lived in rural areas. Specific analytical procedures showed the presence of agricultural pesticides in cerebral cortex samples of these victims. Therefore, it is possible to believe that the exposition to pesticides during pregnancy can produce the same harmful effects as nicotine on the nicotinic acetylcholine receptors. Moreover, alterations of <i>α</i>7-nicotinic acetylcholine receptors receptor expression were also detected in the lungs of many sudden perinatal death victims, allowing to consider even these findings as possible consequence of maternal exposure to toxic factors.
文摘Introduction: Ventriculomegaly is one of the most common abnormalities detected by prenatal ultrasound. This entity can be associated with brain abnormalities and other malformations. In order to perform a good prenatal counseling, the diagnosis is essential. Objective: Our purpose was to report the management of 3 cases of ventriculomegaly in our practice and underline the benefits of the neuropathologic exam. Methods: We analyzed retrospectively 3 medical files concerning fetus that were diagnosed as having one or two ventricles of >10 mm and a follow up for prenatal diagnosis. Results: All cases were diagnosed between 22 and 27 weeks of gestation by an ultrasound. In a case, the ventriculomegaly evolved rapidly to a hydrocephalus. In two cases, the pregnancy was terminated with medical interruption by the parent’s request. Amniocentesis confirmed the diagnosis of congenital toxoplasmosis in case 2 there were no chromosomal abnormalities after karyotyping. Causes included holoprosencephaly, congenital toxoplasmosis and mesencephalosynapsis. Conclusion: Ultrasonography may detect ventriculomegaly nerverthless in the cases presented, pathology exam was essential to assess the diagnostic. Causes are numerous and prognosis variable. We recommand MRI that is more and more accessible in our regions in the follow up of this entity and neuropathology exam in case of termination of the pregnancy. The establishment of main causes of ventriculomegaly in our regions (infectious causes for example) could help to prevent this outcome in our practice.
文摘Hydrocephalus is a heterogeneous, neurological condition characterized by altered flow of cerebrospinal fluid (CSF) that can occur at any age. Neuropathological changes associated with hydrocephalus are dependent on the age of onset, rate of ventricular enlargement, and the etiology. Hydrocephalic brain damage is also influenced by contributions from both mechanical forces and metabolic changes, which increases the heterogeneity of the condition. However, as ventriculomegaly progresses, the surrounding brain tissue is compressed within the cranial vault, elevating intracranial pressure and eventually leading to severe brain damage. From this perspective, it makes sense that periventricular brain regions are the initial sites of damage as ventricular dilatation occurs. The following review of neuropathological changes in hydrocephalus will first discuss cellular and region specific damage from the ventricles and outward towards the cortex and brainstem. This will be followed by vascular and hypoxic changes associated with the condition. Both types of brain impairments are dependent on the severity of the condition, and they will be described accordingly.
文摘The fast aging human population requires new approaches to reliable diagnosis and proper treatment of dementia in elderly patients with psychiatric disorders such as bipolar disorder (BD) and schizophrenia (SCZ). As compared to other psychiatric disorders, BD and SCZ are characterized by increased and similar risk for dementia as well as cerebrovascular (CVD) and Parkinson’s (PD) diseases independent of the patient’s age. There are reports in the literature suggesting BD and SCZ in older patients could cause dementia without contribution from the neurodegenerative diseases, including Alzheimer’s disease (AD), due to the absence of the known neuropathology associated with cognitive decline in such individuals. This view contradicts a plethora of data highlighting AD as a major cause of dementia in the elderly. This issue was addressed by examining postmortem cerebral pathology in an 83-year-old female diagnosed with BD, SCZ, and PD (D1) and comparing it to that of a second donor (D2), an age-matched male diagnosed with Lewy Body Dementia (LBD). Upon thorough histochemical and immunohistochemical examinations of both brains, the PD and LBD diagnoses in D1 and D2 were not confirmed. Instead, AD-related pathology was observed in both subjects with AD advancing to its clinical stage (mild to moderate) only in D1. Diffuse β-amyloid peptide 1-42 (Aβ1-42) staining, most likely reflecting a presence of the Aβ1-42 soluble form, was also detected in cerebellar neurons and cerebellar extracellular space in D1 and D2. Cerebrovascular pathology was pronounced and distinct in both brains and included amyloid angiopathy, hyaline atherosclerosis, microbleeds, and dilated Virchow Robin spaces in D1 as well as thick-walled blood vessels with microbleeds in D2. It was concluded that a mixed AD and cerebrovascular pathology could mimic Lewy Body Disease and potentially contribute to dementia development in elderly BD and SCZ patients.
基金This work was partially supported by National Natural Science Foundation of China(Project No.:82104414)Natural Science Foundation of Guangdong Province of China(Project No.:2022A1515011682)a direct grant from The Chinese University of Hong Kong(Project No.:2021.071).
文摘Gut dysbiosis,a well-known risk factor to triggers the progression of Alzheimer's disease(AD),is strongly associated with metabolic disturbance.Trimethylamine N-oxide(TMAO),produced in the dietary choline metabolism,has been found to accelerate neurodegeneration in AD pathology.In this study,the cognitive function and gut microbiota of TgCRND8(Tg)mice of different ages were evaluated by Morris water maze task(MWMT)and 16S rRNA sequencing,respectively.Young pseudo germ-free(PGF)Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type(WT)mice were selected to determine the role of the gut microbiota in the process of neuropathology.Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions.Our results showed that gut dysbiosis,neuroinflammation response,Ab deposition,tau hyperphosphorylation,TMAO overproduction and cyclin-dependent kinase 5(CDK5)/transcription 3(STAT3)activation occurred in Tg mice age-dependently.Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice,with the activation of CDK5/STAT3 signaling in the brains.On the contrary,faecal microbiota transplantation from WT mice alleviated the cognitive deficits,attenuated neuroinflammation,Ab deposition,tau hyperphosphorylation,TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice.Moreover,excessive choline treatment was also shown to aggravate the cognitive deficits,Ab deposition,neuroinflammation and CDK5/STAT3 pathway activation.These findings provide a novel insight into the interaction between gut dysbiosis and AD progression,clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.
基金Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative(ADNI)(National Institutes of Health Grant U01 AG024904)and DOD ADNI(Department of Defense award number W81XWH-12-2-0012)This study was funded by National Key Research and Development Program of China(Grant No.2016YFC1306600)+3 种基金Zhejiang Provincial Natural Science Foundation of China(Grant Nos.LZ14H180001 and Y16H090026)Young ResearchTalents Fund,Chinese Medicine Science,and Technology Project of Zhejiang Province(Grant No.2018ZQ035)the Fundamental Research Funds for the Central Universities(No.2017XZZX001-01)Zhejiang Medicine and Health Science and Technology Program(2018KY418).
文摘Background:Individuals with subjective memory complaints(SMC)feature a higher risk of cognitive decline and clinical progression of Alzheimer’s disease(AD).However,the pathological mechanism underlying SMC remains unclear.We aimed to assess the intrinsic connectivity network and its relationship with AD-related pathologies in SMC individuals.Methods:We included 44 SMC individuals and 40 normal controls who underwent both resting-state functional MRI and positron emission tomography(PET).Based on graph theory approaches,we detected local and global functional connectivity across the whole brain by using degree centrality(DC)and eigenvector centrality(EC)respectively.Additionally,we analyzed amyloid deposition and tauopathy via florbetapir-PET imaging and cerebrospinal fluid(CSF)data.The voxel-wise two-sample T-test analysis was used to examine between-group differences in the intrinsic functional network and cerebral amyloid deposition.Then,we correlated these network metrics with pathological results.Results:The SMC individuals showed higher DC in the bilateral hippocampus(HP)and left fusiform gyrus and lower DC in the inferior parietal region than controls.Across all subjects,the DC of the bilateral HP and left fusiform gyrus was positively associated with total tau and phosphorylated tau181.However,no significant between-group difference existed in EC and cerebral amyloid deposition.Conclusion:We found impaired local,but not global,intrinsic connectivity networks in SMC individuals.Given the relationships between DC value and tau level,we hypothesized that functional changes in SMC individuals might relate to pathological biomarkers.
基金supported by a Young Investigator Award from the National Alliance for Research on Schizophrenia and DepressionHunter Medical Research Institute,and the National Health and Medical Research Council(NHMRC,Grant No.631057)supported by an NHMRC Senior Research Fellowship(Grant No.1121474).
文摘Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA(miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex(BA 46)(n = 74 matched pairs of schizophrenia, schizoaffective, and control samples)was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92 a, miR-495,and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11 A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that mi RNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.
