Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Phosphoserine is a membrane metabolite that is elevated in Alzheimer's disease brain. This compound has close structural similarity to L-glutamate. Electrophysiological studies indicate that L-phosphoserine has an acute inhibitory effect, but a delayed excitatory action. A hypothesis is developed based on pharmacological and electrophysiological studies that suggest that the inhibition may be mediated through presynaptic inhibition of L-glutamate release or perhaps antagonism of postsynaptic kainic acid receptors. The mechanism of the delayed excitation may lie in the tendency of L-phosphoserine to mimic the action of L-2-amino-4-phosphonobutyric acid, a blocker of chloride- and calcium-sensitive L-glutamate transport. L-Phosphoserine has also been found to be a competitive antagonist at the N-methyl-D-aspartate recognition site and an antagonist of metabotropic receptor-mediated hydrolysis of inositol phospholipids. Because of these actions, there are several potentially important implications for the elevation of L-phosphoserine in Alzheimer's disease, including production memory impairment through presynaptic inhibition of L-glutamate release or blockade of postsynaptic N-methyl-D-aspartate receptors and/or blockade of certain L-glutamate transport sites resulting in increased L-glutamate levels in the synaptic cleft.
Mol Chem Neuropathol 1991 Aug
PMID:Possible roles of L-phosphoserine in the pathogenesis of Alzheimer's disease. 183 14

Hippocampal structures are a major target for adrenal steroid hormones, and hence these neural regions are some of the most likely mediators of the effects of adrenocortical steroids on behavior. Memory disturbance, in particular biasing toward negative contents, are part of the symptomatology presented by depressive patients. In turn, a sizeable subset of depression also presents with hypercortisolemia. Adrenocortical hormones are also known to affect memory processes. Hippocampal formation is essential for declarative memory. We thought it appropriate then to study the effects of adrenal steroids on long-term potentiation, a putative memory mechanism in the hippocampus. Two clearly distinguished components of the evoked response to perforant path stimulation can be studied in the hippocampus: the excitatory postsynaptic potential (EPSP) which denotes the graded depolarization of the somatodendritic region of the neuron and the population spike (PS), a manifestation of the all-or-none-discharge of the cell action potential. Corticosterone had a significant depressant effect on the EPSP component of the evoked response immediately and 15 min after injection. Thereafter EPSP amplitudes were within normal values. Corticosterone significantly decreased the PS immediately after the train, the component remaining low 30 min after the train. 5 alpha-Dihydrocorticosterone (a ring A-reduced metabolite of corticosterone) significantly reduced the PS component of the response at all times after injection. 18-Hydroxydeoxycorticosterone and deoxycorticosterone significantly decreased both EPSP and PS components of the evoked response from the time of infusion. Contrary to expectation, tetrahydrodeoxycorticosterone was ineffective in decreasing and if anything, enhanced the development of long-term potentiation. 18-Hydroxydeoxycorticosterone 21-acetate behaved like vehicle, except for the first 30 min after injection when the EPSP was decreased. Allotetrahydroprogesterone decreased all EPSP's values and had no effect in the PS development in comparison with vehicle. The suggestion is made that the study of steroidal effects on hippocampal LTP can serve as a preclinical model of some aspects of depression in a specific subset of the disease.
Cell Mol Neurobiol 1993 Aug
PMID:Effects of adrenocortical steroids on long-term potentiation in the limbic system: basic mechanisms and behavioral consequences. 825 10

With the arrival of effective symptomatic treatments and the promise of drugs that may delay progression, we now need to identify Alzheimer's disease (AD) at an early stage of the disease. To diagnose AD earlier and more accurately, attention has been directed toward peripheral biochemical markers. This article reviews promising potential cerebrospinal fluid (CSF) biomarkers for AD focussing on their role in clinical diagnosis. In particular, two biochemical markers, CSF total tau (t-tau) protein and the 42 amino acid form of beta-amyloid (Abeta42), perform satisfactorily enough to achieve a role in the clinical diagnostic settings of patients with dementia together with the cumulative information from basic clinical work-up, genetic screening, and brain imaging. These CSF markers are particularly useful to discriminate early or incipient AD from age-associated memory impairment, depression, and some secondary dementias. In order to discriminate AD from other primary dementia disorders, however, more accurate and specific markers are needed. Preliminary evidence strongly suggests that quantification of tau phosphorylated at specific sites in CSF improves early detection, differential diagnosis, and tracking of disease progression in AD.
Mol Neurobiol
PMID:CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. 1183 56

Recent evidence points to the importance of neuropathological and cognitive changes preceding Alzheimer's disease (AD), and clinical trials have begun to focus on preventive treatments designed to slow age-related cognitive decline and delay the onset of AD in people with age-associated memory impairment (AAMI). Studying subjects with few deficits leads to diagnostic heterogeneity and a need for larger samples in order to detect active drug effects. In this report, I review results of recent studies designed to address such issues. Middle-aged and older adults with mild memory complaints were studied using brain imaging and measures of the major known genetic risk for AD, the apolipoprotein E-4 (APOE-4) allele. In a study of positron emission tomography during mental rest, glucose metabolic rates were significantly lower in APOE-4 carriers in brain regions affected by AD. Another study using functional magnetic resonance imaging showed increased brain activation during memory tasks in APOE-4 carriers in similar brain regions. Longitudinal follow-up after 2 yr indicated the potential utility of such brain-imaging measures, combined with genetic-risk information, as surrogate markers in treatment trials for AAMI to prevent further cognitive decline. Current development focuses on novel technologies using positron emission tomography to directly image the neuritic plaques and neurofibrillary tangles of AD in order to provide more specific measures of disease progression in future clinical trials.
J Mol Neurosci
PMID:Brain-imaging surrogate markers for detection and prevention of age-related memory loss. 1221 76

1. In this article we review the studies of memory disabilities in a rat model of Parkinson's disease (PD). 2. Intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. 3. These animals present learning and memory deficits but no sensorimotor impairments, thus modeling the early phase of PD when cognitive impairments are observed but the motor symptoms of the disease are barely present. 4. The cognitive deficits observed in these animals affect memory tasks proposed to model habit learning (the cued version of the water maze task and the two-way active avoidance task) and working memory (a working memory version of the water maze), but spare long-term spatial memory (the spatial reference version of the Morris water maze). 5. The treatment of these animals with levodopa in a dose that restores the striatal level of dopamine does not reverse these memory impairments, probably because this treatment promotes a high level of dopamine in extrastriatal brain regions, such as the prefrontal cortex and the hippocampus. 6. On the other hand, the adenosine receptor antagonist, caffeine, partly reverse the memory impairment effect of SNc lesion in these rats. This effect may be due to caffeine action on nigrostriatal neurons, since it induces dopamine release and modulates the interaction between adenosine and dopamine receptor activity. 7. These results suggest that the MPTP SNc-lesioned rats are a good model to study memory disabilities related to PD and that caffeine and other selective A(2A) adenosine receptor antagonists are promising drugs to treat this symptoms in PD patients.
Cell Mol Neurobiol 2002 Jun
PMID:The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson's disease memory disabilities. 1246 66

The hippocampus is critical for spatial memory formation in rodents. Calcium currents through L-type voltage-sensitive calcium channels (L-VSCCs) are increased in CA1 neurons of the hippocampus of aged rats. We have recently shown that expression of the calcium conducting L-VSCC subunit alpha(1D) (Ca(v)1.3) is selectively increased in area CA1 of aged rats. We and others have speculated that excessive Ca(2+) influx through L-VSCC may be detrimental to memory formation. Therefore, we investigated the relationship between age-related working memory decline and alpha(1D) protein expression in the hippocampus. In addition, we studied the effects of chronic treatment with the L-VSCC antagonist nimodipine (NIM) on age-related working memory deficits and alpha(1D) expression in the hippocampus. Here we report that age-related increases in alpha(1D) expression in area CA1 correlate with working memory impairment in Fischer 344 rats. Furthermore, we demonstrate that chronic NIM treatment ameliorates age-related working memory deficits and reduces expression of alpha(1D) protein in the hippocampus. The present results suggest that L-VSCCs participate in processes underlying memory formation and that increases in L-VSCC protein and currents observed with aging may play a role in age-related memory decline. Furthermore, the amelioration in age-related memory decline produced by NIM treatment may be mediated, at least in part, by reductions in the abnormally high levels of alpha(1D) protein in the aged hippocampus. These findings may have implications for patients with Alzheimer's disease, who show increased L-VSCC protein expression in the hippocampus, and for patients receiving chronic treatment with L-VSCC antagonists.
Brain Res Mol Brain Res 2003 Feb 20
PMID:Age-related working memory impairment is correlated with increases in the L-type calcium channel protein alpha1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment. 1259 Nov 56

Active or passive immunization against the beta-amyloid peptide (Abeta) has been proposed as a method for preventing and/or treating Alzheimer's disease (AD). In addition to lowering brain Abeta and amyloid burden in transgenic mouse models of AD, a beneficial effect of immunization on previously characterized memory impairment(s) has also been reported in these mice. Whether these preclinical data will predict efficacy in AD patients remains to be seen. A clinical trial of active immunization (vaccination) was halted, owing to a serious adverse event (meningoencephalitis), raising questions about the safety of this approach. Two recent reports suggest that immunotherapy-based approaches to treating and preventing AD will require careful antigen and antibody selection, to maximize efficacy and minimize serious adverse events. However, given the potential efficacy of this approach, we believe that immunotherapy for AD should not be prematurely abandoned.
Trends Mol Med 2003 Mar
PMID:Immunotherapy for Alzheimer's disease: will vaccination work? 1265 28

Previous study has demonstrated that the lack of mu-opioid receptor decreased LTP in the dentate gyrus of the hippocampus, suggesting the possibility that the lack of mu-opioid receptor may accompany a change in learning and memory. However, no behavioral study has been undertaken to correlate LTP deficits with spatial memory impairment in mu-opioid receptor knockout mice. Therefore, the present study investigated the hypothesis that mu-opioid receptors contribute to learning and memory by using the Morris water maze, and comparing responses in wild type and mu-opioid receptor gene knockout mice. Our results indicated that mu-opioid receptor knockout mice showed a significant spatial memory impairment compared to wild type in the Morris water maze. This result suggests that the expression of mu-opioid receptor plays an important role in spatial learning and memory examined by Morris water maze.
Brain Res Mol Brain Res 2003 Sep 10
PMID:Impaired water maze learning performance in mu-opioid receptor knockout mice. 1449 82

Endotoxin stimulation of the immune system produces marked alterations in memory functioning. However, molecular links between this cognitive response and infection-responding neurotransmission pathways are still unknown. The cytokine and memory responses of volunteers injected with 0.8 ng/kg Salmonella endotoxin were compared with changes in plasma levels and integrity of the stress-induced acetylcholinesterase variant, AChE-R. Vascular endothelial cells were found to express AChE-R messenger RNA and protein both in healthy and inflamed human tissues. Plasma AChE activity was reduced after endotoxin treatment, but not placebo treatment, parallel to the decline in cortisol after the endotoxin-induced peak and inversely to the accumulation of a C-terminal immunopositive AChE-R peptide of 36 amino acid residues. AChE-R cleavage coincided with significant endotoxin-induced improvement in working memory and impairment in declarative memory. By 3 h posttreatment, working memory improvement was negatively correlated with AChE-R cleavage, which showed association to proinflammatory cytokine levels. By 9 h posttreatment, declarative memory impairment was negatively correlated with AChE-R cleavage and positively correlated with the suppressed AChE activity. Endotoxin-induced peripheral cholinergic stress responses are hence associated with greater impairment in declarative memory and lower improvement in working memory, pointing at AChE-R as a surrogate marker of psychoneuroimmunological stress.
J Mol Neurosci 2003
PMID:Endotoxin-induced changes in human working and declarative memory associate with cleavage of plasma "readthrough" acetylcholinesterase. 1464 87

Central or peripheral administration of the proinflammatory cytokine interleukin (IL)-1beta can impair performance on spatial memory tasks and also elevate circulating concentration of corticosterone. The present experiment provides independent confirmation that intracerebroventricular administration of 10 ng IL-1beta in the rat can have a selective effect on the retrieval of trial unique information about the location of food on an eight-arm radial maze. The probable involvement of corticosterone in IL-1beta-induced memory impairment was indicated by elevated corticosterone levels after IL-1beta administration. Further evidence comes from the blockade of the associated impairment in working memory by coadministration of the glucocorticoid receptor antagonist RU486. Ingestion of diet containing omega-3 fatty acid eicosapentaenoic acid (EPA) is known to antagonize the synthesis of prostaglandin (PG) E2 from aracadonic acid, and the present study confirmed that ethyl EPA (1%) reduced IL-1beta-elevated concentrations of PGE2 and corticosterone. Furthermore, rats given the ethyl-EPA diet for 8 weeks were unaffected by the disruptive effects of IL-1beta on working memory. IL-1beta-induced suppression of mitogen-stimulated release of the anti-inflammatory cytokine IL-10 was also blocked by treatment with ethyl-EPA. Collectively, these data demonstrate that IL-1beta can impair memory function by elevating the concentration of corticosterone and that prior consumption of 1% ethyl-EPA can block both the neuroendocrine and cognitive effects of IL-1beta. These findings in turn may indicate beneficial effects of ethyl-EPA in the treatment of cognitive and affective disorders in which inflammation and stress play a critical role.
Mol Psychiatry 2004 Jun
PMID:Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats. 1469 27


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