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1.
Summary. The activities of hexokinase, aldolase, pyruvate kinase, lactate dehydrogenase and glucose 6-phosphate dehydrogenase were determined in brains of patients with Alzheimer's disease (AD) and in age matched controls. For pyruvate kinase and lactate dehydrogenase a significant increase in specific activity was found in frontal and temporal cortex of AD brains, while the activities of aldolase and hexokinase are not changed. Glucose 6-phosphate dehydrogenase activity was significantly reduced in hippocampus. The increase of some glycolytic enzyme activities is correlated with increased contents of lactate dehydrogenase and glial fibrillary acidic protein (GFAP) in homogenates of frontal and temporal cortex and elevated phosphofructokinase (PFK) and GFAP in astrocytes from the same brain areas. The data extend previous findings on an increase in brain PFK specific activity in AD and suggest that the increased activity of some glycolytic enzymes may be, at least in part, the result of the reactive astrocytosis developing in the course of AD. Received August 3, 1998; accepted November 2, 1998  相似文献   

2.
Removal of the cholinergic innervation to the hippocampus via selective immunolesions of septohippocampal cholinergic neurons induces dysfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis and decreases glucocorticoid receptor (GR) mRNA. This study examined whether removal of the cholinergic innervation decreased GR protein levels and induced changes in the interaction between GR and the cytoplasmic catalytic subunit of protein kinase A (PKAc) in the hippocampus. In lesioned animals, GR protein levels were markedly decreased in the nucleus, but not in the cytosol of hippocampal neurons, whereas mineralocorticoid receptor (MR) levels remained unchanged in both the nucleus and cytosol. PKAc levels did not differ between lesioned and control groups, but PKAc activity was reduced in lesion tissue compared with the controls. The interaction between GR and PKAc was also decreased in the hippocampus without cholinergic input. These results indicate that degeneration of septohippocampal cholinergic neurons leads to reduced PKAc activity in the hippocampus which, in turn, alters GR signaling. The altered GR signaling induced by the degeneration of basal forebrain cholinergic neurons may contribute to dysfunction of the HPA axis in aged animals and patients with Alzheimer's disease (AD) and lead to neuropsychiatric symptoms that occur throughout the course of AD.  相似文献   

3.
Chang Q  Gold PE 《Hippocampus》2004,14(2):170-179
To lesion the cholinergic input to the hippocampus, rats received injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB). The lesions produced near-total loss of choline acetyltransferase (ChAT)-positive neurons in the MS/VDB. The loss was accompanied, however, by only partial decreases (to 40% of control levels) in acetylcholine (ACh) release in the hippocampus. Moreover, ACh release in the hippocampus increased when lesioned and control rats were tested on a spontaneous alternation task, indicating that there was significant residual cholinergic function in the hippocampus. The lesions were sufficient to impair spontaneous alternation scores. However, this impairment could be reversed by either systemic or intra-hippocampal injections of the indirect cholinergic agonist, physostigmine, providing additional evidence of residual and effective cholinergic functions in the hippocampus of lesioned rats. Moreover, systemic injections of physostigmine at doses that produced mild tremors in control rats led to more severe tremors in the lesioned rats, suggesting upregulation of cholinergic mechanisms after saporin lesions, likely in brain areas other than the hippocampus. Thus, these findings provide evidence for decreases in cholinergic input to the hippocampus accompanied by deficits on a spontaneous alternation tasks. The findings also provide evidence for considerable residual cholinergic input to the hippocampus after saporin lesions of the MS/VDB. Together, the results suggest that 192 IgG-saporin lesions of the MS/VDB, using methods often employed, do not fully remove septohippocampal cholinergic input to the hippocampus but are nonetheless sufficient to produce impairments on a task impaired by hippocampal lesions.  相似文献   

4.
An immunohistochemical analysis utilizing antibodies to glial fibrillary acid protein (GFAP), microglia, β-amyloid, amyloid P-component, neurofibrillary tangles (NFT), and microtubule associated protein-tau (MAP-tau) was performed on the cholinergic basal forebrain in Alzheimer’s disease (AD). This severely compromised system, which includes the nucleus basalis of Meynert, is largely responsible for the massive loss of cortical and subcortical cholinergic innervation in the diseased state. Our study juxtaposes the basal forebrain immunohistopathology to the hippocampus, amygdala, and entorhinal cortex in AD. Key findings include a progressive degeneration of these cholinergic neurons charcterized by the formation of immunoreactively atypical NFT, the loss of intraneuronal lipofuscin, a lack of senile plaque and β-amyloid deposition within the basal forebrain, and endstage gliosis without residual extracellular NFT. These structural and compositional differences suggest a unique pathogenesis of the basal forebrain separate from other cortical regions in AD.  相似文献   

5.
Methylphenidate is frequently prescribed for the treatment of attention deficit/hyperactivity disorder. Psychostimulants can cause long-lasting neurochemical and behavioral adaptations. The exact mechanisms underlying its therapeutic and adverse effects are still not well understood. In this context, it was previously demonstrated that methylphenidate altered brain metabolic activity, evaluated by glucose consumption. Most cell energy is obtained through oxidative phosphorylation, in the mitochondrial respiratory chain. Tissues with high energy demands, such as the brain, contain a large number of mitochondria. In this work, our aim was to measure the activities of mitochondrial respiratory chain complexes II and IV and succinate dehydrogenase in cerebellum, prefrontal cortex, hippocampus, striatum, and cerebral cortex of young rats (starting on 25th post-natal day and finishing on 53rd post-natal day) chronically treated with methylphenidate. Our results showed that mitochondrial respiratory chain enzymes activities were increased by chronic administration of this drug. Succinate dehydrogenase was activated in cerebellum, prefrontal cortex and striatum, but did not change in hippocampus and brain cortex. Complex II activity was increased in cerebellum and prefrontal cortex and was not affected in hippocampus, striatum and brain cortex. Finally, complex IV activity was increased in cerebellum, hippocampus, striatum and brain cortex, and was not affected in prefrontal cortex. These findings suggest that chronic exposure to methylphenidate in young rats increases mitochondrial enzymes involved in brain metabolism. Further research is being carried out in order to better understand the effects of this drug on developing nervous system and the potential consequences in adulthood resulting from early-life drug exposure.  相似文献   

6.
Nerve growth factor (NGF) was injected intraventricularly during 4 weeks into adult rats with unilateral partial lesions of the cholinergic septo-hippocampal pathway. On the lesioned side, NGF treatment elevated choline acetyltransferase (ChAT) activity up to 60% above the activity measured on the lesioned side of cytochrome c-treated controls. On the unlesioned side, NGF treatment increased ChAT activity only to an insignificant degree. ChAT activity in the septum of NGF-treated animals was increased by 60% as compared to controls. The NGF-induced increases on the lesioned side and in the septum were not accompanied by elevations in acetylcholinesterase (AChE) activity. Furthermore, histochemical analysis revealed no difference in AChE staining pattern or intensity between NGF-treated and control animals. The lack of effect on AChE strongly suggests that the increases in ChAT activity in hippocampus and septum are due to an elevation of ChAT activity within cholinergic neurons surviving the lesion rather than to a promotion of sprouting of cholinergic fibers.  相似文献   

7.
中枢胆碱能系统损害对脑自由基水平的影响   总被引:4,自引:0,他引:4  
在中枢胆碱能系统损害所致的Alzheimer病模型中,观察不同时期脑组织自由基水平的变化。结果表明,随着时间的推移,中枢胆碱能系统变性逐渐加重,所测到的动物自由基代谢紊乱也越明显;与胆碱能系统联系最密切的海马区超氧化物歧化酶(SOD)及谷胱甘肽过氧化物酶(GSH—PX)活性下降最显著。而自由基代谢紊乱反过来又可能加重神经递质代谢障碍,促使或加重Alzheimer病(AD)的进程。  相似文献   

8.
The septal-hippocampal cholinergic pathway of the rat was either electrically stimulated or lesioned in order to study whether or not acetylcholine turnover rate (TRACh) changes with the activity of the cholinergic neurons. Appropriate electrical stimulation of the septum selectively increased the TRACh in the hippocampus in nonanesthetized and in barbiturate-treated animals. The ACh content of the hippocampus increased by approximately 30% 1 h after fimbria lesions, but decreased by about 80% 9 days after fimbria lesions. Acute fimbria lesions decreased the TRACh in the lesioned side by approximately 85%, but the TRACh in the intact side and in the cortex was unchanged. The same was true in rats with chronic fimbria lesions. In conclusion, the hippocampal TRACh increases or decreases proportionally to the activity of the cholinergic neurons; therefore the measurement of this parameter is of particular value in understanding how postynaptic cholinergic neurons are modulated by putative neurotransmitter released from afferent nerve terminals.  相似文献   

9.
Fluorescence immunohistochemistry was performed to characterize the distribution and phenotype of GLUT8-positive neurons in rat brain and to compare the cellular distribution of GLUT8 with GLUT3 in the hippocampus. Based upon the absence of co-localization with the non-neuronal markers GFAP (astroglial) and OX42 (microglial), it appears that GLUT8 is expressed exclusively in neurons. At the cellular level, GLUT8 immunofluorescence was localized to neuronal cell bodies and the most proximal dendrites of inhibitory and excitatory neurons while GLUT3 immunofluorescence was localized to the neuropil in the hippocampus. These results demonstrate that GLUT8 is a neuron-specific glucose transporter expressed in the neuronal cell bodies of excitatory and inhibitory neurons in the rat hippocampus.  相似文献   

10.
Changes in the interaction between sex hormones and the cholinergic system are presumed to play a role in cognitive decline in aging and Alzheimer's disease (AD). The hippocampus is one of the most strongly affected brain structures in AD and the vertical limb of the diagonal band of Broca (VDB) is its major source of innervation. In the present study we found, surprisingly, for the first time that the neuronal metabolic activity as measured by the size of the Golgi apparatus in the VDB gradually increases after the age of 50 years in controls and that this process starts earlier and is more pronounced in Alzheimer's disease patients. Neuronal metabolic activity in the VDB was significantly higher in AD than in control patients younger than 70 years of age and was higher in control patients over 70 years than in control patients younger than 70 years of age. The activation of VDB neurons during aging was accompanied by an increased nuclear estrogen receptor (ER) beta staining, which was stronger in patients over 70 years of age than in younger subjects (in both controls and AD patients). Interestingly, as in the nucleus basalis of Meynert, nuclear ERalpha expression was markedly enhanced in AD patients compared to controls independent of age. In addition, evidence was found for the influence of APOE genotype on ERalpha and ERbeta staining in the human VDB in aging and in AD. APOE genotype was positively correlated (epsilon 2 < epsilon 3 < epsilon 4) with the percentage of cytoplasm ERalpha-positive VDB neurons in elderly control male and female subjects and with both nuclear and cytoplasm ERbeta-positive neurons in control women. In conclusion, the VDB is compensatory activated and shows more nuclear ER expression in aging and AD in a sex- and APOE genotype-dependent way. So neither global degeneration or a strongly decreased neuronal metabolism nor a lack of sex hormone receptors in the VDB seems to contribute to the decline in cognition in aging or AD in which the hippocampus plays such a crucial role.  相似文献   

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