Excess manganese (Mn) in brain can be neurotoxic, implicated in several neurodegenerative disorders such as sporadic Alzheimer's disease (AD). However, little is known about the altered metal environment including elevated Mn in the progressive cognitive impairment of AD. Indeed, whether high Mn is associated with AD risk remains elusive. In the study, we recruited 40 Chinese elders with different cognitive statuses and investigated concentrations of Mn in whole blood and plasma amyloid-ß (Aß) peptides. Surprisingly, there were significant correlations of Mn with Mini-Mental State Examination score and Clinical Dementia Rating Scale score. In addition, plasma Aß peptides increased with elevated Mn. Further studies both in vitro and in vivo demonstrated dose-related neurotoxicity and increase of Aß by Mn treatment, which was probably caused by disrupted Aß degradation. These data suggested that high Mn may be involved in the progress of AD as an essential pathogenic factor.
Alzheimer Disease/complications , Cognition Disorders/metabolism , Manganese/adverse effects , Manganese/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/chemically induced , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Case-Control Studies , Cell Line, Tumor , Cognition Disorders/genetics , Cognition Disorders/pathology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Humans , L-Lactate Dehydrogenase/metabolism , Male , Maze Learning/drug effects , Maze Learning/physiology , Mental Status Schedule , Mice , Mice, Transgenic , Mutation/genetics , Neuroblastoma/pathology , Presenilin-1/genetics
OBJECTIVE: To investigate the relationship between different distribution of NMDA receptor subunits and motor neurons selective vulnerability in amyotrophic lateral sclerosis. METHODS: First we investigated whether administration of THA, a glutamate transport inhibitor, in cultured organotypic brain tissue made different damage of motor cortex and piriform cortex. Then we testified that selective motor cortex injury was related to disparate distribution of NR2A and NR2B by measuring their protein expression with the method of Western blot. In order to make clear different role of NR2A and NR2B in chronic glutamate excitotoxicity of motor neurons injury, we inhibited NR2A and NR2B separately in cultured cortical motor neurons and brain slices to investigate the mortality changes of motor neurons. RESULTS: The mortality rate of neurons in motor cortex was apparently higher than that of piriform cortex (64.50% ± 2.19% and 30.43% ± 4.75%, P<0.01) after cultured brain slices were damaged by THA 100 µmol/L for two weeks. Western blot results showed that protein expression of NR2B/NR2A ratio in motor cortex was prominently higher than that of piriform cortex (0.87 ± 0.09 and 0.47 ± 0.09, P<0.01). In inhibitor protective experiments, NR2B inhibitor showed positive effects. The mortality rates of cultured cortical motor neurons in control, glutamate, glutamate + NR2A inhibitor, glutamate + NR2B inhibitor were 6.85% ± 1.47%,47.48% ± 5.75%, 45.76% ± 8.09%, 18.10% ± 3.11%, respectively. The mortality rates of cultured motor cortex slices in control, THA, THA + NR2A inhibitor, THA + NR2B inhibitor were 12.49% ± 2.09%,100%,110.87% ± 15.76%, 35.13% ± 5.32%, respectively. CONCLUSION: NR2A and NR2B subunits play different roles in motor neurons chronic glutamate excitotoxicity. Intensive distribution of NR2B subunit in motor cortex makes motor neurons selectively vulnerable to glutamate excitotoxicity in amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis/metabolism , Cerebral Cortex/metabolism , Motor Neurons/pathology , Receptors, N-Methyl-D-Aspartate/metabolism , Amino Acid Transport System X-AG/antagonists & inhibitors , Amyotrophic Lateral Sclerosis/pathology , Animals , Animals, Newborn , Cells, Cultured , Cerebral Cortex/cytology , Fetus , Glutamic Acid/pharmacology , Mice , Mice, Inbred C57BL , Motor Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
OBJECTIVE: To investigate significance of Nogo-A in atrophic muscle fibers in diagnosis of amyotrophic lateral sclerosis (ALS). METHODS: Forty cases which were diagnosed definitely by clinical, pathological or DNA analysis were included. All of the cases underwent muscle biopsies in order to carry out Nogo-A immunostaining. RESULTS: Nogo-A expression was detected in the atrophic muscle fibers but in either neurogenic disease or myogenic disease, the atrophic muscle fibers demonstrated expression of Nogo-A. As compared with the stainings of NADH-TR and ATPase, it was showed that Nogo-A positive fibers were mainly type I fibers. CONCLUSION: Our results show that the presence of Nogo-A in diseased human muscle biopsies is not limited to ALS, therefore it cannot be the standard for ALS diagnosis.
Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/metabolism , Muscle, Skeletal/metabolism , Myelin Proteins/biosynthesis , Atrophy , Humans , Muscle, Skeletal/pathology , Nogo Proteins
