Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excitatory amino acid transporters (EAATs) maintain the balance between pathological and physiological conditions by limiting the extracellular concentration of glutamate within the CNS and thus preventing excitotoxic injury. The loss of EAAT2 has been associated with the development of neurological diseases such as amyotrophic lateral sclerosis. It has therefore been suggested that the over-expression of specific EAATs may provide some degree of neuroprotection. However, the inability to isolate and study the function of the different EAAT isoforms in a cell type-specific manner has made it difficult to determine the exact contribution of individual EAATs toward neuroprotection or neurodegeneration in the context of excitotoxic injury. To address this question, we transduced hippocampal slice cultures from 1-week-old C57B/6 mice with recombinant adeno-associated virus carrying an EAAT2 gene expression cassette. EAAT2 gene expression was driven in neurons with the neuron-specific enolase promoter. Using this model system, we were able to induce a significant increase in the expression of functional EAAT2. Consequently, a significant increase in CA1 neuronal damage was observed in slices over-expressing EAAT2 in neurons following an acute exposure to exogenous glutamate. These data suggest that the increased expression of EAAT2 within neurons may contribute to neurodegeneration.
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PMID:Over-expression of the human EAAT2 glutamate transporter within neurons of mouse organotypic hippocampal slice cultures leads to increased vulnerability of CA1 pyramidal cells. 1586 27

We report the autopsy findings of a 62-year-old man who exhibited progressive FTD 10 years before the appearance of muscle weakness and wasting, and who died approximately 11 years after onset of the symptoms. Degeneration and atrophy of the frontal and temporal lobes, which contained ubiquitin-positive neuronal inclusions and dystrophic neurites, were evident. Circumscribed degeneration affecting the hippocampal CA1-subiculum border zone was also a feature. Moreover, degeneration was present in both the upper and lower motor neuron systems, the latter being more severely affected. A few lower motor neurons were found to contain the cytoplasmic inclusions characteristic of ALS (i.e. Bunina bodies and ubiquitin-positive skeins). Also of interest was the presence of pallidonigroluysian atrophy, which appeared to be responsible for the chorea-like involuntary movements that developed in this patient approximately 2 months before death. The clinical and pathological features of our patient further support the idea that motor neuron disease-inclusion dementia (MND-ID), which has been classified as a pathological subgroup of FTD, is a forme fruste of ALS with dementia. In other words, if patients with MND-ID live long enough, they may develop ALS.
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PMID:Is motor neuron disease-inclusion dementia a forme fruste of amyotrophic lateral sclerosis with dementia? An autopsy case further supporting the disease concept. 1619 38

Although amyotrophic lateral sclerosis (ALS) is mainly considered as a motor disease, extramotor neural and cognitive alterations have also been reported in ALS patients. There is evidence that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are implicated in about 20% of familiar ALS and transgenic mice overexpressing the human Cu/Zn superoxide dismutase (GLY(93) --> ALA) mutation show an ALS-like phenotype. However, while motor behavior has been extensively analyzed in these mutants, little is known on their cognitive abilities. To characterize the pre-symptomatic cognitive profile of G93A+/+ mice, we estimated their capability to detect spatial novelty and examined several indexes of their hippocampal function. We found an enhancement of spatial abilities in mutant mice associated with (1) a higher expression of hippocampal AMPA subunit GluR1 mRNA and of GluR1 protein levels, and (2) an increased induction and maintenance of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Thus, before leading to extensive neuronal excitotoxicity, the high endogenous levels of glutamate present in the brain of pre-symptomatic G93A+/+ mice could mediate site-specific molecular and synaptic changes providing favorable conditions to spatial information processing. These findings suggest that identification of pre-symptomatic behavioral changes in murine models of ALS may point to early neural abnormalities selectively associated with mutations in the Cu/Zn superoxide dismutase (SOD1) gene.
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PMID:Molecular and synaptic changes in the hippocampus underlying superior spatial abilities in pre-symptomatic G93A+/+ mice overexpressing the human Cu/Zn superoxide dismutase (Gly93 --> ALA) mutation. 1630 74

As dementing diseases are too numerous to refer to all of them, I confine my description to the neuropathology of amyotrophic lateral sclerosis with dementia (ALSD), and cerebral vascular pathology of three unique vascular diseases causing dementia. 1) ALSD: The cortical neuropathology of this condition exhibit two main unique profiles in addition to mainly temporal lobe-located cortical changes. One is ubiquitin-positive intraneuronal cytoplasmic inclusions, and the other a localized neuronal degeneration in the transitional zone between the hippocampal CA1 and subiculum. 2) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): The characteristic vascular change of this condition is marked intimal thickening of the middle and small arteries with relatively preserved smooth muscle cells in the media. The scalp arteries escape this lesion, indicating non-ischemic pathomechanisms for the baldness seen in this condition. 3) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): The main lesions of the cerebral vessels are smooth muscle cell degeneration of deep perforating and small meningeal arteries with deposition of granular osomiophilic material in the media of the affected vessels. 4) Sneddon syndrome: This condition characterized by livedo reticularis and recurrent multiple infarctions shows marked sclerotic changes in the deep perforating arterioles and main cerebral arteries with relatively spared middle- and small-sized meningeal arteries.
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PMID:[Neuropathology associated with dementia]. 1644 31

The presence of many neurofibrillary tangles (NFTs) in the central nervous system is a hallmark of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in people living in the Kii peninsula of Japan and in the island of Guam. To determine whether or not ALS and PDC are on a spectrum of a single tauopathy, we investigated the topography of NFTs semiquantitatively in two patients with ALS, three with PDC, and two with "PDC plus ALS" (PDC followed by ALS) on the basis of clinical symptoms. NFTs were counted under x100 magnification of Gallyas-Braak stained preparations and were plotted on brain maps of the hemisphere, brainstem, and the spinal cord. In all cases, the hippocampus, particularly in the CA1 field, the parahippocampal gyrus, amygdaloid nucleus, and the temporal poles were most severely affected. In the neocortex, layers II-III were more severely affected by NFTs than layers V-VI. In the spinal cord, a few NFTs were revealed in the intermediate gray. NFTs were dense in all cases of PDC and "PDC plus ALS" and variable in density in ALS cases, although the topography was similar between them. We conclude that similar topographical distribution of NFTs in ALS and PDC in people living in the Kii peninsula of Japan suggests a single tauopathy.
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PMID:Similar topographical distribution of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-dementia complex in people living in the Kii peninsula of Japan suggests a single tauopathy. 1727 50

Patients with ALSD show characteristic mental and behavioral changes, represented by lack of insight into their tragic condition. Psychiatric symptoms usually precede life-threatening motor neuron symptoms. Cerebral SPECT, especially 3D-SSP, exercises its power in the diagnosis of ALSD by demonstrating constant and sharp blood flow reduction in the prefrontal region. The neuropathology of the cerebral cortex is characterized by most prominent and probably earliest degeneration in the medial side cortex of the temporal pole, border zone between the CA1 and subiculum, ambient gyrus, and amygdala as well as cytoplasmic ubiquitinated inclusion bodies in the dentate gyrus granular neurons and other cortical small neurons. Motoneuron pathology is almost the same as that in classic ALS except for more prominent Bunina bodies and less affected pyramidal tract. The substantia nigra is usually degenerated without Lewy bodies. A condition recently proposed as motor neuron disease-inclusion dementia seems to be a forme froste of ALSD. Several cases of ALSD exhibited upper motor neuron-dominant involvement, showing the possibility that the category of ALSD may be widened than considered so far.
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PMID:[Amyotrophic lateral sclerosis with dementia (ALSD)]. 1743 90

Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD(2), PGI(2), and PGF(2alpha) receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI(2) and TXA(2) receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl-d-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.
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PMID:Divergent effects of prostaglandin receptor signaling on neuronal survival. 1757 54

In the present study, we used the SOD1(G93A) mutant transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS) and performed immunohistochemical studies to investigate the changes of insulin-like growth factor-binding protein 4 (IGFBP4) in the central nervous system. Decreased expression of IGFBP4 was obvious in the cerebral cortex, hippocampus, cerebellar cortex and inferior olive of SOD1(G93A) transgenic mice. In the cerebral cortex, there was a significant decrease in IGFBP4 immunoreactivity in the pyramidal cells. In the hippocampal formation, IGFBP4 immunoreactivity was also decreased in the pyramidal cells of CA1-3 areas and the granule cells of dentate gyrus. In the cerebellar cortex, IGFBP4 immunoreactivity was prominent in the granular layer in wtSOD1 transgenic mice, compared to that in SOD1(G93A) transgenic mice. IGFBP4 immunoreactivity was decreased in the inferior olive of SOD1(G93A) transgenic mice. This study, showing decreased IGFBP4 in different brain regions of SOD1(G93A) transgenic mice, may provide clues to understanding the differential susceptibility of neural structures in ALS, suggesting a role of IGFBP4 in an abnormality of cognitive and/or motor function in ALS. The mechanisms and functional implications of these decreases require elucidation.
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PMID:Immunohistochemical study on the distribution of insulin-like growth factor-binding protein 4 in the central nervous system of SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis. 1882 65

In the present study, we performed immunohistochemical studies to investigate the changes of insulin-like growth factor binding protein 2 (IGFBP2) in the central nervous system of SOD1(G93A) mutant transgenic mice as an in vivo model of amyotrophic lateral sclerosis (ALS). Decreased immunoreactivity for IGFBP2 was observed in the cerebral cortex, hippocampus and brainstem of SOD1(G93A) transgenic mice. In the cerebral cortex, the number of IGFBP2-positive cells was decreased in the somatomotor area, somatosensory area, auditory area, visual area, entorhinal area, piriform area and prefrontal area. In the hippocampal formation, IGFBP2 immunoreactivity was significantly decreased in the CA1-3 areas and the dentate gyrus. In the brainstem, few IGFBP2-immunoreactive cells were observed in the medullary and pontine reticular formation, vestibular nucleus, trigeminal motor nucleus, facial nucleus, hypoglossal nucleus and raphe nucleus. In the spinal cord, IGFBP2 immunoreactivity was not significantly decreased in SOD1(G93A) transgenic mice. This study showing decreased IGFBP2 in different brain regions of SOD1(G93A) transgenic mice may provide clues for understanding differential susceptibility of neural structures in ALS.
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PMID:Immunohistochemical localization of insulin-like growth factor binding protein 2 in the central nervous system of SOD1(G93A) transgenic mice. 1946 44

Loss of basal forebrain cholinergic innervation of the hippocampus and severe neuronal loss within the hippocampal CA1 region are early hallmarks of Alzheimer's disease, and are strongly correlated with cognitive status. Various therapeutic approaches involve attempts to enhance neurotransmission or to provide some level of neuroprotection for remaining cells. An alternative approach may involve the generation of new cells to replace those lost in AD. Indeed, a simple shift in the balance between cell generation and cell loss may slow disease progression and possibly even reverse existing cognitive deficits. One potential neurogenic regulator might be acetylcholine, itself, which has been shown to play a critical role in hippocampal development. Here, we report the effects of various cholinergic compounds on indices of hippocampal neurogenesis, demonstrating a significant induction following pharmacological activation of muscarinic M1 receptors, located on hippocampal progenitors in the adult brain. This is the first report that a small-molecule agonist may induce neurogenesis in the hippocampal CA1 region. Furthermore, such treatment reversed deficits in markers of neurogenesis and spatial working memory triggered by cholinergic denervation in a rodent model. This study suggests the use of small molecule, receptor agonists may represent a novel means to trigger the restoration of specific neuronal populations lost to a variety of neurodegenerative disorders, such as Parkinson's, Alzheimer's, Huntington's and Amyotrophic Lateral Sclerosis.
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PMID:Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation. 2002 37


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