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Biomedical subjects

C Hock

Publications and source records attributed to C Hock.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells.

Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer's disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl2) on oxidative stress, cell cytotoxicity, beta-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 microg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n = 13, p<0.001). Preincubation of cells for 30 min with 1 microM melatonin or premixing melatonin and HgCl2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that 50 microg/L HgCl2 for 24 h produced a 50% inhibition of MTT reduction (n = 9, p<0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MTT reduction equaling control levels. The release of beta-amyloid peptide (Abeta) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl2 was shown to be different: Abeta 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Abeta 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n = 9, p<0.001). Preincubation of cells with melatonin resulted in an attenuation of Abeta 1-40 and Abeta 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n = 9, p<0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD.

Amyloid beta-Peptides↗
PubMed2000

High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.

Clinical differential diagnosis of early-onset dementia (EOD) includes familial Alzheimer disease (FAD) and hereditary prion disease. In both disease entities, postmortem brain histopathological examination is essential for unambiguous diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and amyloid precursor protein (APP) are associated with FAD, whereas mutations in the prion protein (PrP) gene are associated with prion disease. To investigate the proportion of EOD attributable to known genes, we prospectively (i.e., antemortem) screened these four genes for mutations by sequencing genomic PCR products from patients with EOD before age 60 years. Family history for dementia was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1, F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously reported mutations (in APP, in three patients who were most likely unrelated, V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1 of the 17 patients with NFH. We conclude that because of the lack of specific antemortem diagnostic markers for FAD and hereditary prion disease, all four genes should be included in a molecular diagnostic program in patients with EOD who had PFH.

Adult↗
PubMed2000

Cytokines and neurotrophins interact in normal and diseased states.

Neurotrophins (NTs) such as nerve growth factor (NGF) as well as cytokines, for example, interleukin-6 (IL-6), are communicators between the nervous and immune systems. There is evidence for mutual interactions between NTs and cytokines. Strategies are being developed to elucidate the molecular mechanism/s of interactions and to understand how cytokines are involved in health and disease. Analysis of underlying signaling pathways in glial cells indicates that different transcription factors, such as NF-kappa B, cAMP-responsive-element binding protein (CREB), and activator protein 1 (AP-1), are involved in NT induction. IL-6 and NTs of the NGF family are coexpressed at sites of nerve injury. Interactions of these factors could modulate both neuronal de- and regeneration: IL-6 in conjunction with its soluble IL-6 receptor induces a specific pattern of NTs in astrocytes in defined brain regions. This indicates that the IL-6 system mediates a local supply of NTs that participate in diverse CNS functions, such as protection of neurons from insults, neuronal survival, and neuroimmune responses.

Animals↗
PubMed2000

High frequency of mutations in four different disease genes in early-onset dementia.

Heterozygous mutations in the genes for amyloid precursor protein (APP), the presenilins (PS1, PS2), prion protein (PrP), neuroserpin, and tau are associated with early-onset dementia (EOD) with or without neurological signs in the early disease stage. To investigate the proportion of EOD without early neurological signs attributable to known genes we prospectively (i.e., ante mortem) screened these six genes for mutations in 36 patients with EOD before age 60. Family history for dementia was positive (PFH) in 16, negative (NFH) in 17, and unknown (UFH) in 3 patients. In 12 patients, we found 5 novel mutations (PS1: F105L; PS2: T122P, M239I; PrP: Q160X, T188K) and 5 previously reported mutations (APP: in three most likely unrelated patients V717I; PS1: A79V, M139V; PrP: P102L, T183A) that all are considered disease causing. Of these 12 patients, 9 had PFH. This indicates a detection rate of 56% (9/16) in patients with PFH. We found 2 mutations (APP V717I) in 2 of the 3 the UFH-patients, and only 1 mutation (PrP T188K) in 1 of the 17 patients with NFH. No mutation was found in tau and neuroserpin genes. To date, three patients died and FAD, predicted by PS mutations in two patients, and prion disease, predicted by a PrP mutation in the third one, were histopathologically confirmed at autopsy. Up to now, mutation findings may be the most specific biomarkers for an ante mortem diagnosis of FAD or hereditary prion disease.

Age of Onset↗
PubMed2000

Treatment with the selective muscarinic agonist talsaclidine decreases cerebrospinal fluid levels of total amyloid beta-peptide in patients with Alzheimer's disease.

Brain amyloid load in Alzheimer's disease (AD) is, at least in genetic forms, associated with overproduction of amyloid beta-peptides (A beta). Thus, lowering A beta production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as beta-, gamma-, and alpha-secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic alpha-secretase pathway in model systems. Talsaclidine was administered double-blind, placebo-controlled, and randomized to 24 AD patients and cerebrospinal fluid (CSF) levels of total A beta were quantitated before and after 4 weeks of drug treatment. We observed that talsaclidine decreases CSF levels of A beta significantly over time within the treatment group (n = 20) by a median of 16% as well as compared to placebo (n = 4) by a median of 27%. We conclude that treatment with selective M1 agonists may reduce A beta production and may thus be further evaluated as a potential amyloid-lowering therapy of AD.

Aged↗
PubMed2000

Alterations in trk A, trk B and trk C receptor immunoreactivities in parietal cortex and cerebellum in Alzheimer's disease.

The neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 bind to the tyrosine kinase (trk) receptors trk A, trk B and trk C, respectively, with high affinity. We investigated the expression of the trk receptors in the parietal cortex (PC) and cerebellum of patients with Alzheimer's disease (AD) and age-matched controls. Cortical layers II-VI displayed a distinct cellular immunoreactivity for trk A and C with an emphasis in the pyramidal neurons of layers III and V. Trk B immunoreactivity was primarily located in the deeper cortical layers with a predominance in layer V. There was a decrease in trk A and C immunoreactivity in the PC of AD cases, while trk B density appeared to be unchanged. In addition, cerebellar Purkinje cells revealed a distinct immunoreactivity for trk C both in control and AD cases, suggesting trk C may be important in the maintenance of these cells in the aged brain.

Aged↗
PubMed1999

Rapid cortical hemoglobin deoxygenation after heroin and methadone injection in humans: a preliminary report.

The short-term effects of intravenous opioids (heroin 20-300 mg, methadone 30-180 mg) on cortical hemoglobin oxygenation were examined by near infrared spectroscopy in ten opioid-dependent subjects and were compared with the effects of saline in ten age-matched normal controls. Heroin and methadone produced a rapid and dramatic decrease in cortical hemoglobin oxygenation. Saline had no effects. Opioid-induced acute deoxygenation of cortical hemoglobin is most likely associated with respiratory depression. Thorough medical monitoring is strongly recommended in intravenous opioid maintenance treatments.

Adult↗
PubMed1999

A rapid-cycling bipolar patient treated with long nights, bedrest, and light.

BACKGROUND: Stabilization of rapid-cycling bipolar disorder is extremely difficult. METHODS: A refractory bipolar I rapid-cycling patient on valproate was treated with long "nights" (extended sleep in darkness) and daytime light therapy. RESULTS: Rapid cycling immediately stopped on initiation of a 10 hour dark/rest period. This was extended to 14 hours (plus a self-selected 1 hour midday nap) without problems. Depression gradually improved when midday light therapy was added; near-euthymia was attained after light therapy was shifted to the morning. CONCLUSIONS: Nonpharmacological chronobiological treatments may be a means to interrupt rapid cycling.

Activity Cycles↗
PubMed1999

Risk factors and differential diagnosis of Alzheimer's disease.

Due to demographic changes the frequency of dementia is increasing dramatically. About 50-60% of patients with dementia are clinically associated with AD, which is a multifactorial and long-term disease both in clinical and preclinical aspects. Various genetic and non-genetic risk factors play a role in influencing age of onset and disease progression.

Aged↗
PubMed1999

ELISA-quantitation of phosphorylated tau protein in the Alzheimer's disease brain.

A reliable, sensitive and specific sandwich ELISA for the quantitation of paired helical filament (PHF) tau in human brain was developed using well-defined monoclonal antibodies. We examined rapid-autopsy-derived brain tissue from 21 neuropathologically confirmed Alzheimer's disease (AD) patients and 14 nondemented controls, matched for age, sex and postmortem delay times. We demonstrated significant elevations of phosphorylated tau levels in the frontal and parietal cortex as well as in the hippocampus of AD patients as compared to the nondemented controls. No difference was observed in the cerebellum. Phosphorylated tau levels measured by ELISA were significantly correlated with the presence or absence of neurofibrillary tangles.

Aged↗
PubMed1998

Decreased trkA neurotrophin receptor expression in the parietal cortex of patients with Alzheimer's disease.

The cholinergic neurons of the basal forebrain system are sensitive to nerve growth factor (NGF), a member of the neurotrophin gene family. Since the cholinergic system is affected early in the course of Alzheimer's disease (AD), it was hypothesized that a deficit in NGF, e.g. reduced neurotrophin uptake by specific receptors, may play a role in neuronal cell death in AD. We quantitated mRNA levels of neurotrophins (NGF, BDNF, NT-3, NT-4/5) and their receptors (trkA, trkB, trkC, p75) in AD postmortem parietal cortex (n = 16) and cerebellum (n = 11). We applied highly sensitive reverse transcription-polymerase chain reaction (RT-PCR) in rapid autopsy derived brain tissue (mean postmortem delay 147+/-96 min., n = 53) to minimize postmortem mRNA variations. In the AD parietal cortex trkA mRNA levels were more than two times lower as compared to controls (n = 16, mean+/-SEM 0.26+/-0.07 units/S12, range, 0-1.78, and n = 11, 0.59+/-0.10 units/S12, range, 0.17-1.10, respectively, P = 0.015). TrkA mRNA levels did not appear to be altered in the AD cerebellum as compared to normal human cerebellum. NGF, BDNF, NT-3, NT-4/5, as well as trkB, trkC and p75 mRNA levels were unchanged in AD parietal cortex and cerebellum as compared to controls. This finding suggests that a reduced expression of the trkA receptor may contribute to impaired NGF-trkA signalling and a reduced transport of NGF in cholinergic neurons. These results reveal a central specific role of the high affinity NGF receptor during neurodegeneration in AD.

Aged↗
PubMed1998

Increased blood mercury levels in patients with Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder that leads to dementia and death. In addition to several genetic parameters, various environmental factors may influence the risk of getting AD. In order to test whether blood levels of the heavy metal mercury are increased in AD, we measured blood mercury concentrations in AD patients (n = 33), and compared them to age-matched control patients with major depression (MD) (n = 45), as well as to an additional control group of patients with various non-psychiatric disorders (n = 65). Blood mercury levels were more than two-fold higher in AD patients as compared to both control groups (p = 0.0005, and p = 0.0000, respectively). In early onset AD patients (n = 13), blood mercury levels were almost three-fold higher as compared to controls (p = 0.0002, and p = 0.0000, respectively). These increases were unrelated to the patients' dental status. Linear regression analysis of blood mercury concentrations and CSF levels of amyloid beta-peptide (A beta) revealed a significant correlation of these measures in AD patients (n = 15, r = 0.7440, p = 0.0015, Pearson type of correlation). These results demonstrate elevated blood levels of mercury in AD, and they suggest that this increase of mercury levels is associated with high CSF levels of A beta, whereas tau levels were unrelated. Possible explanations of increased blood mercury levels in AD include yet unidentified environmental sources or release from brain tissue with the advance in neuronal death.

Aged↗
PubMed1998

Inflammatory signals induce neurotrophin expression in human microglial cells.

Inflammatory processes involving reactive microglia, e.g., those associated with beta-amyloid containing neuritic and core plaques in Alzheimer's disease, appear to contribute to neuronal degeneration in the CNS. The fact that increased nerve growth factor (NGF) protein levels were found throughout brains of Alzheimer's disease patients led us to investigate neurotrophin synthesis in a human microglial cell line showing typical properties of human microglial cells, including expression of neurotrophins such as NGF, as well as the NGF receptor trkA and the low-affinity neurotrophin receptor p75. We found that the cytokines interleukin-1beta and tumor necrosis factor-alpha synergistically stimulate microglial NGF transcription and protein release. Moreover, exposure of microglial cells to complement factor C3a induces NGF expression. To assess the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in inflammatory mediator-induced microglial NGF expression, the effect of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) was analyzed. In the presence of PDTC, a dose-dependent inhibition of cytokine-activated NGF expression occurred. In contrast, the C3a-dependent stimulation of NGF synthesis was not influenced by PDTC. In addition, microglial neurotoxicity-mediating beta-amyloid peptides A beta(1-40) and A beta(1-42) failed to alter NGF synthesis, whereas A beta(25-35) specifically induced NF-kappaB-dependent microglial NGF expression. In conclusion, inflammatory signals (cytokines and complement factors), as well as A beta(25-35), are potent stimulators of human microglial NGF synthesis involving NF-kappaB-dependent and -independent mechanisms. Microglial secretion of neurotrophins appears to be involved in early processes of neuronal regeneration.

Amyloid beta-Peptides↗
PubMed1998

Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease.

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.

Alleles↗
PubMed1998

Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer's disease and major depression - inverse correlation with dementia severity.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive dementia that ultimately leads to death. Histopathological hallmarks of AD include brain amyloid deposits and neurofibrillary tangles. Major depression is a frequent diagnosis in every gerontopsychiatric clinic that sees patients with both cognitive and affective disorders. Many depressed patients, in fact, are clinically characterized by cognitive impairments. Thus, an assay that excludes - or confirms - probable AD in cognitively impaired patients is desirable. Such assays may use protein markers that are derived from such histopathologically relevant molecules as the amyloid precursor protein (APP) and its derivatives including the amyloid beta-peptides (Abeta). To evaluate the differential diagnostic properties of cerebrospinal fluid (CSF) Abeta and secreted soluble ectodomain (APPs), we quantitated CSF levels of these measures in AD patients and compared them to age-matched control patients with major depression. CSF levels of APPs and Abeta were similar in patients with AD or major depression, and the apolipoprotein E genotype had no influence on CSF levels of Abeta in AD patients. Measurement of Abeta peptide using a novel zinc/copper capture ELISA that detects aggregated Abeta peptides as well demonstrated similar levels in AD and major depression. In AD patients, CSF levels of total Abeta (Abeta1-40 plus Abeta1-42) were inversely correlated with a functional measure of dementia severity (NOSGER), suggesting that CSF levels of Abeta decrease with advancing severity of AD. Thus, CSF levels of Abeta are not useful for the differentiation of AD from major depression. However, CSF levels of Abeta reflect the severity of dementia and may be useful as biological markers of the stage of the disease.

Aged↗
PubMed1998

Histological markers in nasal mucosa of patients with Alzheimer's disease.

Neuropathological changes such as dystrophic neurites and the presence of abnormal tau protein in the olfactory system, including primary sensory cells and nerve fibres have previously been demonstrated in nasal mucosa tissue of patients with Alzheimer's disease (AD). These changes were detected in autopsy-derived material from histopathologically confirmed AD cases as well as in biopsy tissue from clinical severely ill AD patients. To investigate the potential usefulness for the early diagnosis of AD, we obtained biopsy tissue from olfactory mucosa from 5 clinically mild to moderate AD patients and stained for the presence of tau or beta-amyloid by immunocytochemistry using a panel of specific antibodies. No positive staining was found in any of the cases. For comparison, post-mortem olfactory tissue from AD patients with severe neuropathological changes (widespread neurofibrillary tangles and amyloid in the brain) was investigated. In these severe cases, tau immunoreactivity was found in fine nerve fibres in the lamina propria and in a few olfactory epithelial cells. These results are consistent with other reports showing that cytoskeletal changes and tau pathology in the olfactory epithelium are not primary (or specific) features of AD and may occur predominantly in late stages of the disease.

Aged↗