Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Alzheimer's disease-related beta-amyloid precursor protein (beta-APP) is metabolized to a number of potentially amyloidogenic peptides that are believed to be pathogenic. Application of relatively low concentrations of the soluble forms of these peptides has previously been shown to block high-frequency stimulation-induced long-term potentiation (LTP) of glutamatergic transmission in the hippocampus. The present experiments examined how these peptides affect low-frequency stimulation-induced long-term depression (LTD) and the reversal of LTP (depotentiation). We discovered that beta-amyloid peptide (Abeta1-42) and the Abeta-containing C -terminus of beta-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus. The LTD was frequency- and NMDA receptor-dependent. Thus, although low-frequency stimulation alone was ineffective, after intracerebroventricular injection of Abeta1-42, it induced an LTD that was blocked by d-(-)-2-amino-5-phosphonopentanoic acid. Furthermore, an NMDA receptor-dependent depotentiation was induced in a time-dependent manner, being evoked by injection of CT 10 min, but not 1 hr, after LTP induction. These use- and time-dependent effects of the amyloidogenic peptides on synaptic plasticity promote long-lasting reductions in synaptic strength and oppose activity-dependent strengthening of transmission in the hippocampus. This will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.
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PMID:Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. 1116 Apr 3

With the development of new treatments, there is an increasing need for early diagnosis of sporadic Alzheimer's disease. Therefore, biological markers allowing positive diagnosis early in the course of the disease are highly desirable. Cerebrospinal fluid levels of protein tau were shown to be significantly increased in patients with Alzheimer's disease. Although sensitivity is high, poor specificity limits the diagnostic value of this marker. The same is true for the 42 amino acid isoform of beta-amyloid protein that is significantly decreased in cerebrospinal fluid of Alzheimer's disease patients. However, combining both markers could improve specificity at least allowing differentiation between Alzheimer's disease, normal ageing and depressive pseudodementia. Other biological markers such as cerebrospinal fluid levels of neurotransmitters, cytokines or superoxide dismutase were shown to have even less diagnostic value. The apolipoprotein epsilon 4 allele is a risk factor for Alzheimer's disease but not a diagnostic marker as many individuals who inherit epsilon 4 do not develop the disease. Till now, a single diagnostic marker allowing discrimination between Alzheimer's disease and other dementias does not exist. Combined cerebrospinal fluid levels of beta-amyloid protein and tau protein might be used as a marker that helps discriminating Alzheimer's disease from normal ageing and depression.
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PMID:Biological and genetic markers of sporadic Alzheimer's disease. 1133

We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.
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PMID:APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. 1156 12

Recent studies indicate that the Tg2576 transgenic mouse model of Alzheimer's disease [tg(hAPP)] demonstrates disturbances in plasma glucose and neuroendocrine function reminiscent of Alzheimer's disease (AD). Alterations in any one of these systems can have a profound effect on hepatic cytochrome P450 (CYP) expression. Additionally, the recent discovery that amyloid beta 1-42 can induce the expression of CYP reductase in neuronal cultures further suggests that hepatic CYP-related metabolism may be affected by the expression of mutant human amyloid precursor protein in these tg(hAPP) mice. Therefore, the current study was conducted to investigate the activity and protein content of several CYP isoforms in the livers and kidneys of aged (20-month-old) tg(hAPP) mice. tg(hAPP) mice exhibit significant elevations in hepatic CYP2B, CYP2E1-, CYP3A- and CYP4A-associated activities and CYP4A immunoreactive protein compared with wild-type. In contrast to the liver, a significant depression in renal CYP2E1- and CYP4A-associated activities were demonstrated in tg(hAPP) mice. The presence of the mutant hAPP protein was detected in the brain, kidney and livers of tg(hAPP) mice.
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PMID:Elevated hepatic and depressed renal cytochrome P450 activity in the Tg2576 transgenic mouse model of Alzheimer's disease. 1184 64

Glucocorticoids are key elements in the maintenance of an organism's homeostasis, a dynamic balance that is constantly challenged by internal and external stressors. Chronic exposure to elevated glucocorticoids may induce profound effects on an individual's physical and mental well-being. Therefore, a complex neuroendocrine system, the limbic-hypothalamo-pituitary-adrenocortical (LHPA) axis, exists to regulate glucocorticoid homeostasis. Dysregulation of the LHPA axis has been linked to numerous psychiatric disorders, including eating disorders, anxiety, depression, posttraumatic stress disorder, memory impairment, neurodegenerative disorders, and even Alzheimer disease. At a molecular level, the actions of glucocorticoids are mediated by two different cytoplasmic receptors, the mineralocorticoid receptor and the glucocorticoid receptor. These corticosteroid receptors are heteromeric complexes found in dynamic association with a still growing number of chaperone proteins and other factors mediating their actions. Because this dynamic association is extremely sensitive to changes in cellular environment, energy, and metabolic state, we hypothesize that these corticosteroid receptors act as "sensor" signal transducers critical for homeostasis. In this review, we focus on the interplay among protein folding, transport, and function of the corticosteroid receptors at the cellular level, which provides a foundation for understanding the pathogenesis of glucocorticoid resistance or hypersensitivity, causing imbalances in the LHPA axis, and possibly triggering psychiatric disorders.
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PMID:Corticosteroid receptors: a dynamic interplay between protein folding and homeostatic control. Possible implications in psychiatric disorders. 1239 67

Major depression remains difficult to treat, despite the wide array of registered antidepressants available. In recent years there has been a surge in the popularity of natural or alternative medications. Despite this growing popularity, there is limited evidence for the effectiveness of many of these natural treatments. S-adenosyl-L-methionine (SAMe) is one of the better studied of the natural remedies. SAMe is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. Derived from the amino acid L-methionine through a metabolic pathway called the one-carbon cycle, SAMe has been postulated to have antidepressant properties. A small number of clinical trials with parenteral or oral SAMe have shown that, at doses of 200-1600 mg/d, SAMe is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses. SAMe may have a faster onset of action than do conventional antidepressants and may potentiate the effect of tricyclic antidepressants. SAMe may also protect against the deleterious effects of Alzheimer disease. SAMe is well tolerated and relatively free of adverse effects, although some cases of mania have been reported in bipolar patients. Overall, SAMe appears to be safe and effective in the treatment of depression, but more research is needed to determine optimal doses. Head-to-head comparisons with newer antidepressants should help to clarify SAMe's place in the psychopharmacologic armamentarium.
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PMID:Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. 1242 Jul 2

Recently, a novel risk gene protein expressed in elderly patients with the diagnosis of Alzheimer disease (AD) was discovered on chromosome 21 within the APP (amyloid precursor protein) region. This 79 amino acid protein, ALZAS (Alzheimer Associated Protein) contains the beta-amyloid peptide 1-42 fragment, the APP transmembrane signal, and a unique 12 amino acid c-terminal which is not present in any known allele of the APP gene. Reverse transcription-PCR revealed that the transcript of ALZAS was expressed in cortical and hippocampal regions of human Alzheimer disease brain as well as in leukocytes derived from AD patients. Most specifically, an endogenous antibody was found in patients with confirmed AD, in patients with depression, and in subjects suggested to have presymptomatic AD, where it was directed against epitopes within the intron encoded amino acid c-terminal sequence.
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PMID:A broader horizon of Alzheimer pathogenesis: ALZAS--an early serum biomarker? 1245 54

A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
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PMID:APP processing and synaptic function. 1267 Apr 22

DEPRESSION IN THE PATIENT: Signs of depression in patients with Alzheimer's disease are difficult to detect because they change over time and vary in intensity and duration. Estimated frequency depends greatly on the evaluation scale (Cornell scale, Geriatric Depression Scale, Behave-Alzheimer disease scale, Cohen-Mansfield scale, Neuropsychiatric Inventory (NPI)). Several risk factors have been identified including early age of disease onset, female gender, etc). The anatomic basis of depression is essentially related to the noradrenergic and serotoninergic systems. DEPRESSION IN THE CAREGIVER: Caregivers bear a heavy burden, psychologically (30-50% of all cases of depression), physically, and financially. Depression in the caregiver favors depression in the patient, and vice versa. Episodes may develop at any time during the disease course. Decompensation depends on both patient-related and caregiver-related factors. IMPORTANCE OF DETECTING DEPRESSION: Depression is frequent, both in the patient and in the caregiver and must be detected and treated early. It has been demonstrated that 50% of the caregivers may be affected, but only 10-20% are treated.
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PMID:[Epidemiology of depression in patients with Alzheimer's disease and in their caregivers]. 1294 1

The central nervous system has the second highest concentration of lipids after adipose tissue. Long chain fatty acids, particularly arachidonic acid and docosahexaenoic acid, are integral components of neural membrane phospholipids. Alterations in neural membrane phospholipid components cannot only influence crucial intracellular and intercellular signaling but also alter many membrane physical properties such as fluidity, phase transition temperature, bilayer thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly affects neurotransmission, membrane-bound enzyme and ion channel activities, gene expression, intensity of inflammation, and immunity and synaptic plasticity. Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the molecular mechanism of docosahexaenoic acid involvement in the disorders remains unknown, the supplementation of docosahexaenoic acid in the diet restores gene expression and modulates neurotransmission. Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease.
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PMID:Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. 1504 Oct 28


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