Sublethal concentrations of prion peptide PrP106-126 or the amyloid beta peptide of Alzheimer's disease activates expression of proapoptotic markers in primary cortical neurons.

Neurodegenerative disorders such as prion diseases and Alzheimer's disease (AD) are characterized by neuronal dysfunction and accumulation of amyloidogenic protein. In vitro studies have demonstrated that these amyloidogenic proteins can induce cellular oxidative stress and therefore may contribute to the neuronal dysfunction observed in these illnesses. Although the neurotoxic pathways are not fully elucidated, recent studies in AD have demonstrated up-regulation of caspases in neurons treated with amyloid beta (Abeta) peptide, suggesting involvement of apoptotic processes.

Sex differences and the HPA axis: implications for psychiatric disease.

Depression is twice as common in women as in men. Given that stress plays a major role in the onset of this disorder, sex differences in the response to stress could influence women's vulnerability to depression. The data presented suggest that greater stress responsiveness in women may be influenced by ovarian steroids.

A predicted cortical serotonergic/cholinergic/GABAergic interface as a site of pathology in schizophrenia.

1. The pathological process that precipitates schizophrenia has yet to be identified. However, many lines of evidence suggest that a change in the functioning of the frontal cortex is an important abnormality that underlies schizophrenia.

A proposed pathological model in the hippocampus of subjects with schizophrenia.

1. The hippocampal formation plays an important role in the normal functioning of the brain, being implicated in cognition and sensory gating, both of which are affected in schizophrenia. The hippocampal formation receives information from the association cortices, which is processed by glutamatergic transmission within the hippocampus.

The "chip" as a specific genetic tool.

DNA microarrays are powerful tools for the analysis of the organization and regulation of the brain, in both illness and health. Such messenger RNA expression methods are outgrowths of a marriage between the several genome sequencing projects and a wide variety of physical, chemical, optical, and electronic systems. The advantages of microarray analyses include the ability to study the regulation of several genes or even the entire genome in a single experiment.

Biological markers and schizophrenia.

Objective: The delivery of biological markers for schizophrenia would greatly assist preventative strategies by identifying at-risk individuals who could then be monitored and treated in a manner with a view to minimising subsequent morbidity. This paper aims to present a selection of biological measures that may indicate risk of schizophrenia.

Method: A selective and brief review is provided of intensively studied putative markers, including enlarged cerebral ventricles, dopamine D2 receptor density, amphetamine-stimulated central nervous system dopamine release, plasma homovanillic acid and smooth pursuit eye tracking dysfunction.

Children's experience of violence in China and Korea: a transcultural study.

Objective: There were two aims: First, to compare children's rates of being battered in home, by peers, and by teachers among students between China and Korea, and second, to identify particular risk factors for such violence.

Methods: Children in grades four through six in Shanghai (238 cases) and Yanji (245 cases) in China and Seoul (248 cases) and Kimpo (241 cases) in Korea were surveyed by questionnaire method. They were asked to complete the Straus' Conflict Tactics Scale and their frequencies in the three situations respectively, and other demographic items.

Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation.

Background: Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients.

Oxidative processes in Alzheimer's disease: the role of abeta-metal interactions.

Alzheimer's disease is characterized by signs of a major oxidative stress in the neocortex and the concomitant deposition of Amyloid beta (Abeta). Abeta is a metalloprotein that binds copper, and is electrochemically active. Abeta converts molecular oxygen into hydrogen peroxide by reducing copper or iron, and this may lead to Fenton chemistry.

Signal transmission, rather than reception, is the underlying neurochemical abnormality in schizophrenia.

Objective: This review aims to summarise the outcome of studies on changes in the molecular architecture of the brain of subjects with schizophrenia and formulate a hypothesis on mechanisms involved in the pathology of the illness.

Method: The outcomes from key studies using neuroimaging techniques and tissue obtained post-mortem that have been directed toward identifying abnormalities in the molecular architecture of the brain in subjects with schizophrenia were summarised. Using the results from these studies hypotheses were formulated on the underlying pathological process that precipitate schizophrenia.

Serotonin(2A) receptors are reduced in the planum temporale from subjects with schizophrenia.

[(3)H]ketanserin binding to 5HT(2A) receptors was measured in the left planum temporale (sensory speech cortex) from schizophrenic and non-schizophrenic (control) subjects using both particulate membranes and tissue sections. There was a significant decrease in the affinity of [(3)H]ketanserin binding to particulate membranes from schizophrenic subjects who were treated with phenothiazines up to death. Adding 2nM chlorpromazine to brain tissue from control subjects caused a similar decrease in the affinity of [(3)H]ketanserin binding to particulate membranes.

The amino-terminal cyclic nucleotide binding site of the type II cGMP-dependent protein kinase is essential for full cyclic nucleotide-dependent activation.

For the type I cGMP-dependent protein kinases (cGKIalpha and cGKIbeta), a high affinity interaction exists between the C2 amino group of cGMP and the hydroxyl side chain of a threonine conserved in most cGMP binding sites. To examine the effect of this interaction on ligand binding and kinase activation in the type II isozyme of cGMP-dependent protein kinase (cGKII), alanine was substituted for the conserved threonine or serine. cGKII was found to require the C2 amino group of cGMP and its cognate serine or threonine hydroxyl for efficient cGMP activation.

Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia.

Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.

A spreadsheet for the calculation of comprehensive statistics for the assessment of diagnostic tests and inter-rater agreement.

While advances in statistical methods allow greater insight into the characteristics of diagnostic tests and of raters, researchers frequently rely on incomplete or inappropriate indices of performance. Lack of available computer software is probably an important barrier to optimal use of data collected to evaluate diagnostic tests and agreement between raters. A spreadsheet has been designed to provide comprehensive statistics for the assessment of diagnostic tests and inter-rater reliability when these investigations yield data that can be summarized in a 2x2 table.

Neurobiological findings in early phase schizophrenia.

This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice (1.5 mm) study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi (right -9%, left -11%) in first episode patients that were of a similar magnitude to those found in chronic patients (right -10%, left -11%) but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses.

What the evolution of the amyloid protein precursor supergene family tells us about its function.

The Alzheimer's disease amyloid protein precursor (APP) gene is part of a multi-gene super-family from which sixteen homologous amyloid precursor-like proteins (APLP) and APP species homologues have been isolated and characterised. Comparison of exon structure (including the uncharacterised APL-1 gene), construction of phylogenetic trees, and analysis of the protein sequence alignment of known homologues of the APP super-family were performed to reconstruct the evolution of the family and to assess the functional significance of conserved protein sequences between homologues. This analysis supports an adhesion function for all members of the APP super family, with specificity determined by those sequences which are not conserved between APLP lineages, and provides evidence for an increasingly complex APP superfamily during evolution.

The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia.

Clinical studies of cholinergic pharmacotherapy, together with the putative role of the muscarinic receptor system in the neurophysiology of human behavior, support a possible muscarinic cholinergic involvement in schizophrenia. The present study has measured the density of [3H]AF-DX 384 labelled receptors (muscarinic M2 and M4) in the caudate-putamen, obtained at autopsy, from 19 subjects who had schizophrenia, and 20 subjects who did not have schizophrenia. [3H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects (104 +/- 10.

No change in the density of the serotonin1A receptor, the serotonin4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex from subjects with schizophrenia.

Changes in serotonin receptors and the serotonin transporter have been reported in the dorsolateral prefrontal cortex from subjects with schizophrenia, an area of the brain thought to be important in the pathology of the illness. To further our understanding on how such changes could play a role in the pathology of the illness, in situ radioligand binding with autoradiography was used to measure the density of the serotonin1A receptor, the serotonin4 receptor and the serotonin transporter in the dorsolateral prefrontal cortex, obtained at autopsy, from 10 schizophrenic and 10 control subjects. The binding of [3H]8-OH-DPAT to serotonin1A receptor, [3H]GR113808 to the 5HT4 receptor and [3H]citalopram to serotonin transporter was not altered in subjects with schizophrenia.

Cyclic AMP- and cyclic GMP-dependent protein kinases differ in their regulation of cyclic AMP response element-dependent gene transcription.

The ability of cGMP-dependent protein kinases (cGKs) to activate cAMP response element (CRE)-dependent gene transcription was compared with that of cAMP-dependent protein kinases (cAKs). Although both the type Ibeta cGMP-dependent protein kinase (cGKIbeta) and the type II cAMP-dependent protein kinase (cAKII) phosphorylated the cytoplasmic substrate VASP (vasodilator- and A kinase-stimulated phosphoprotein) to a similar extent, cyclic nucleotide regulation of CRE-dependent transcription was at least 10-fold higher in cAKII-transfected cells than in cGKIbeta-transfected cells. Overexpression of each kinase in mammalian cells resulted in a cytoplasmic localization of the unactivated enzyme.

Familial prion disease mutation alters the secondary structure of recombinant mouse prion protein: implications for the mechanism of prion formation.

A considerable body of data supports the model that the infectious agent (called a prion) which causes the transmissible spongiform encephalopathies is a replicating polypeptide devoid of nucleic acid. Prions are believed to propagate by changing the conformation of the normal cellular prion protein (PrPc) into an infectious isoform without altering the primary sequence. Proteins equivalent to the mature form of the wild-type mouse prion protein (residues 23-231) or with a mutation equivalent to that associated with Gerstmann-Straüssler-Scheinker disease (proline to leucine at codon 102 in human; 101 in mouse) were expressed in E.

Recombinant human amyloid precursor-like protein 2 (APLP2) expressed in the yeast Pichia pastoris can stimulate neurite outgrowth.

The human amyloid precursor-like protein 2 (APLP2) is a member of the Alzheimer's disease amyloid precursor protein (APP) gene family. The human APLP2 ectodomain (sAPLP2) was expressed in the yeast Pichia pastoris and the recombinant sAPLP2 was purified from the culture medium in a single step by metal-chelating Sepharose chromatography. The neuritotrophic activity of APLP2 was compared to the APP isoforms sAPP695 and sAPP751 on chick sympathetic neurones.

Survival of cultured neurons from amyloid precursor protein knock-out mice against Alzheimer's amyloid-beta toxicity and oxidative stress.

Studies on the amyloid precursor protein (APP) have suggested that it may be neuroprotective against amyloid-beta (Abeta) toxicity and oxidative stress. However, these findings have been obtained from either transfection of cell lines and mice that overexpress human APP isoforms or pretreatment of APP-expressing primary neurons with exogenous soluble APP. The neuroprotective role of endogenously expressed APP in neurons exposed to Abeta or oxidative stress has not been determined.

Clozapine and olanzapine treatment decreases rat cortical and limbic GABA(A) receptors.

The density of GABA(A) receptors in the hippocampus and the temporal cortex from rats treated for 28 days with either haloperidol, chlorpromazine, clozapine or olanzapine was measured. Compared to haloperidol (0.01 and 0.

Effects of the amyloid protein precursor of Alzheimer's disease and other ligands of the LDL receptor-related protein on neurite outgrowth from sympathetic neurons in culture.

The amyloid protein precursor (APP) of Alzheimer's disease can stimulate neurite outgrowth in vitro. The receptor responsible for this effect has not been identified. Kunitz protease inhibitor (KPI)-containing forms of APP bind to the low-density lipoprotein receptor-related protein (LRP).