Pathways to the discovery of the Abeta amyloid of Alzheimer's disease.

Many participants played a role in discovering the composition and sequence of the Abeta amyloid of Alzheimer's disease. This sequence enabled the cloning of the amyloid precursor protein (APP), which elucidated its proteolytic origin from the membrane of neurons. The proteolytic enzymes which process APP and the Abeta fragment itself are now the prime validated drug targets for therapeutic intervention.

Serotonin 1a receptor and associated G-protein activation in schizophrenia and bipolar disorder.

Abnormalities in the serotonergic signalling system, including the serotonin 1a receptor, have been implicated in the pathogenesis of schizophrenia and bipolar 1 disorder. However, there is no consensus on whether the density of the serotonin 1a receptor and/or the activity of the G-proteins linking the receptor to the intracellular cascade are altered in these disease states. To address these issues, tissue obtained postmortem from four cortical regions was used to measure [3H] 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) binding and 8-OH-DPAT-stimulated guanosine 5'-[gamma-thio]triphosphate (GTPgammaS) binding to determine if either parameter is altered in schizophrenia or bipolar I disorder.

Self-paced saccades and saccades to oddball targets in Parkinson's disease.

Patients with Parkinson's disease (PD) manifest difficulty in initiation and execution of movements, particularly when movements are sequential, simultaneous or repetitive. Eye movements are particularly effective in evaluating motor impairments. We utilized a series of saccadic eye movement paradigms to explore the ability of 13 patients with mild-moderate PD and 13 age-matched healthy controls to self-pace saccades between two continuously illuminated targets, before and after an externally cued tracking period, and respond to unexpected changes in task demand.

SCH 23390 in the prefrontal cortex enhances the effect of apomorphine on prepulse inhibition of rats.

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.

Overexpression of Abeta is associated with acceleration of onset of motor impairment and superoxide dismutase 1 aggregation in an amyotrophic lateral sclerosis mouse model.

Transgenic mice carrying mutant Cu/Zn superoxide dismutase (SOD1) recapitulate the motor impairment of human amyotrophic lateral sclerosis (ALS). The amyloid-beta (Abeta) peptide associated with Alzheimer's disease is neurotoxic. To investigate the potential role of Abeta in ALS development, we generated a double transgenic mouse line that overexpresses SOD1(G93A) and amyloid precursor protein (APP)-C100.

Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder.

Objective: In order to identify whether the mechanisms associated with neurotransmitter release are involved in the pathologies of bipolar disorder and schizophrenia, levels of presynaptic [synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin, vesicle-associated membrane protein, dynamin I] and structural (neuronal cell adhesion molecule and alpha-synuclein) neuronal markers were measured in Brodmann's area 9 obtained postmortem from eight subjects with bipolar I disorder (BPDI), 20 with schizophrenia and 20 controls.

Methods: Determinations of protein levels were carried out using Western blot techniques with specific antibodies. Levels of mRNA were measured using real-time polymerase chain reaction.

Regionally specific changes in levels of cortical S100beta in bipolar 1 disorder but not schizophrenia.

Objective: To determine if levels of the glial-derived proteins S100beta and glial acidic fibrillary protein (GFAP) and the pro- and antiapoptotic proteins p53 and Bcl-2 were altered in the cortex of subjects with schizophrenia or bipolar 1 disorder.

Method: Levels of S100beta, GFAP, p53 and Bcl-2 were measured in cortex (Brodmann's Areas (BAs) 9, 10, 46 and 40) of control subjects and subjects with schizophrenia, bipolar 1 disorder and in the cortex of rats treated with haloperidol or lithium using protein-specific antibodies and western blot analysis.

Results: Levels of S100beta were decreased in BA 9 and increased in BA 40 from subjects with bipolar 1 disorder.

In vitro gamma-secretase cleavage of the Alzheimer's amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc.

The gamma-secretase complex mediates the final proteolytic event in Alzheimer's disease amyloid-beta biogenesis. This membrane complex of presenilin, anterior pharynx defective, nicastrin, and presenilin enhancer-2 cleaves the C-terminal 99-amino acid fragment of the amyloid precursor protein intramembranously at gamma-sites to form C-terminally heterogeneous amyloid-beta and cleaves at an epsilon-site to release the intracellular domain or epsilon-C-terminal fragment. In this work, two novel in vitro gamma-secretase assays are developed to further explore the biochemical characteristics of gamma-secretase activity.

No change in cortical muscarinic M2, M3 receptors or [35S]GTPgammaS binding in schizophrenia.

Muscarinic M1, but not M4, receptors have been shown to be decreased in Brodmann's area (BA) 9 obtained postmortem from subjects with schizophrenia. This study extends that data by measuring levels of muscarinic M2 and M3 receptor protein and mRNAs in BA 9 and BA 40 from the same cohorts of subjects used in the study of M1 and M4 receptors. In addition, the ability of carbachol to stimulate muscarinic receptors that signal through the Gi/o G-proteins was measured in BA 9 from the same cohorts of subjects.

N-Ethylmaleimide sensitive factor in the cortex of subjects with schizophrenia and bipolar I disorder.

N-Ethylmaleimide sensitive factor (NSF) is a presynaptic protein that has been suggested to be differentially expressed in the cortex of schizophrenic subjects through both high-throughput proteomic and genomic screening studies. Thus, to expand upon these studies we measured NSF using Western blotting in four regions of the cortex (BA9, 10, 40 and 46), in a cohort comprising 20 schizophrenic subjects, 8 bipolar I disorder subjects, and 20 control subjects. There was no significant difference in NSF levels between diagnostic cohorts in any of the four cortical regions.

Importance of animal models in schizophrenia research.

Objective: This review aims to summarize the importance of animal models for research on psychiatric illnesses, particularly schizophrenia.

Method And Results: Several aspects of animal models are addressed, including animal experimentation ethics and theoretical considerations of different aspects of validity of animal models. A more specific discussion is included on two of the most widely used behavioural models, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition, followed by comments on the difficulty of modelling negative symptoms of schizophrenia.

Clozapine decreases [3H] CP 55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens.

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs.

Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder.

Postmortem CNS studies have suggested an uncoupling of the gamma-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA(A) receptor in schizophrenia. The GABA(A) receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA(A) receptor would be a change in receptor subunit composition.

Cortical glutamatergic markers in schizophrenia.

Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate receptors (N-methyl D-aspartate, [3H]CGP39653, [3H]MK-801), amino-3-hydroxy-5-methyl-4-isoxazole ([3H]AMPA), kainate ([3H]kainate), and the high-affinity glutamate uptake site ([3H]aspartate) using in situ radioligand binding with autoradiography and levels of mRNA for kainate receptors using in situ hybridization in the dorsolateral prefrontal cortex from 20 subjects with schizophrenia and 20 controls matched for age and sex. Levels of [3H]kainate binding were significantly decreased in cortical laminae I-II (p = 0.

Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder.

Background: This study extends an initial finding of increased levels of apoE in Brodmann's area (BA) 9 from subjects with schizophrenia to determine if apoE is altered in other brain regions and in brains from subjects with bipolar I disorder (BID).

Methods: ApoE was quantified apoE in BA 9, 10, 40, 46 and caudate putamen from control (n = 18), schizophrenic (n = 19) and BID (n = 8) subjects using Western blotting.

Results: In schizophrenia, there was increased apoE in BA9 (mean +/- SEM: schizophrenia 3.

Transition-state analogue gamma-secretase inhibitors stabilize a 900 kDa presenilin/nicastrin complex.

Gamma-secretase mediates the final step, which generates Alzheimer's disease Abeta amyloid protein, by cleaving the transmembrane domain of the amyloid-beta protein precursor. Four gene products, presenilin, nicastrin, APH-1, and PEN-2, are required for gamma-secretase activity that is contained within a high molecular mass complex. To further characterize gamma-secretase, we probed membranes from human neuroblastoma SH-SY5Y cells with gamma-secretase inhibitor biotin derivatives of L-685,458, pepstatin A, and the difluoro alcohol 1-Bt.

Hippocampal 5-hydroxytryptamine receptors: abnormalities in postmortem brain from schizophrenic subjects.

There is strong evidence that hippocampal 5-hydroxytryptamine (5-HT) systems are affected in schizophrenia and hence we have studied a number of markers of the 5-HT system in hippocampi from subjects with schizophrenia. Using in situ radioligand binding with autoradiography we measured [(3)H]proplyamino-8-hydroxy-1,2,3,4-tetrahydronapthalene, [(3)H]ketanserin and [(3)H]sumatriptan binding in hippocampi from 20 schizophrenic and 20 control subjects. There were significant decreases in the density of [(3)H]ketanserin binding to the 5-HT(2A) receptor (5-HT(2A)R) in the Cornu Ammonis (CA) 3 (p=0.

Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex.

We have analysed the expression of a truncated variant presenilin 2 protein (PS2V) in frontal cortex from subjects with Alzheimer's disease (AD) and age-matched controls, and compared these results with cortex from bipolar disorder (BP), schizophrenia (SZ) and controls in a second brain bank collection. PS2V protein was detected as a 14 kDa species with antibodies directed to the PS2 N-terminal region and to the new C-terminus created by alternative transcription. PS2V protein levels were significantly increased by two-fold in AD cortex, as compared to age-matched controls.

Identifying vulnerability markers in prodromal patients: a step in the right direction for schizophrenia prevention.

Research has shown that many of the long-term deficits that are observable in schizophrenia populations are present prior to the emergence of psychotic symptoms. Recent research suggests schizophrenia has a "prodromal" period, whereby significant changes from premorbid functioning can be observed. Accurate classification of this period could have far-reaching implications for schizophrenia prevention.

HPA axis activation in major depression and response to fluoxetine: a pilot study.

Hypothalamic-pituitary-adrenal (HPA) axis activation is a frequently observed phenomenon in major depression. However, whether this activation has any implications for treatment is unknown. To address this question, we examined baseline response to metyrapone and 6-week response to fluoxetine.

A review of psychosocial outcomes for patients seeking cosmetic surgery.

The authors reviewed the literature on psychological and psychosocial outcomes for individuals undergoing cosmetic surgery, to address whether elective cosmetic procedures improve psychological well-being and psychosocial functioning and whether there are identifiable predictors of an unsatisfactory psychological outcome. They conducted a search of appropriate computerized databases for studies that evaluated psychological and psychosocial status both before and after elective cosmetic surgery. They identified 37 relevant studies of varying cosmetic procedures that utilized disparate methodologies.

Measurement of dopamine D2-like receptors in postmortem CNS and pituitary: differential regional changes in schizophrenia.

In situ radioligand binding with autoradiography and anti-human dopamine D(2) receptor antibodies with Western blots have been used to measure the density of dopamine D(2)-like receptors in the caudate-putamen and pituitary from schizophrenic subjects who did or did not have residual antipsychotic drugs in their tissue at death. There was a significant decrease in the Ki for haloperidol displaceable [(125)I]iodosulpride binding in the pituitary (p < 0.01) and caudate-putamen (p < 0.

Neurodegenerative diseases and oxidative stress.

Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species.