Abeta(25-35) attenuated SREBP level in nuclear extracts of serum-deprived human neuroblastoma cells.

Disturbance in cholesterol homeostasis appears to be an important factor in the pathogenesis of neurodegenerative disorders. The aim of the present study was to investigate sterol regulatory element binding protein (SREBP) levels in the nuclear extracts of human neuroblastoma cells and the possible interaction of beta-amyloid peptide (Abeta) and cholesterol with this transcription factor. In this study, cultured human neuroblastoma cells (SHSY-5Y) were incubated in serum-deprived media in the presence or absence of Abeta((25-35)) (1 microM) or cholesterol (300 microM) for 24 h.

Amyloid imaging in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder of which the exact cause is still not known. There has, however, been remarkable progress in the understanding of the pathophysiological events that underlie the disease with a focus on amyloid formation. We do not know yet if amyloid is the most crucial target for an effective therapy in AD.

Ammonia, a selective agent for methane production by syntrophic acetate oxidation at mesophilic temperature.

In biogas processes, methane production from acetate proceeds by either aceticlastic methanogenesis or through syntrophic acetate oxidation (SAO). In the present study, the pathway for methane production from acetate was analysed; i) during a gradual increase of the ammonia concentration (final concentration 7 g NH(4)(+) -N/L) in a semi-continuous lab-scale anaerobic digester (4.3 L), operating at mesophilic temperature (37 degrees C) or ii) in diluted enrichment cultures (100 ml) experiencing a gradual increase in ammonia, sodium, potassium and propionic acid.

Synergistic effect of apolipoprotein E epsilon4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer's disease.

Objective: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI).

Methods: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses.

Towards more efficient testing strategies--analyzing the efficiency of toxicity data requirements in relation to the criteria for classification and labelling.

This contribution is based on the assumption that the aim of toxicity testing as required by chemicals legislation is to identify as many chemicals of concern to human health and the environment as possible, given a limited amount of resources allocated to testing. Based on this assumption we propose a method for the optimization of test systems for industrial chemicals, based on the calculation of efficiency ratios for tests and test systems. The efficiency ratio of a toxicity test depends on the monetary cost of performing the test and the probability that the test will identify a chemical of concern, as estimated by the rules for classification and warning labelling.

Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease.

Objective: The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function.

Methods: The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30 mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5 mg/day) and the phenserine group remained on phenserine.

Amyloid plaque imaging in vivo: current achievement and future prospects.

Introduction: Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment.

Unidirectional Influx and Net Accumulation of PIB.

The compound {N-methyl-[(11)C]}2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, "PIB", measured by positron emission tomography, has been demonstrated to image brain beta-amyloid deposition in Alzheimer's disease (AD). In the present study the benefit of measuring the PIB accumulation rate together with the unidirectional influx of PIB into the brain was investigated in healthy control subjects and patients with AD. In a monkey changes in the influx rate constant K(1) of PIB closely followed changes in CBF, caused by alteration of Pa(CO2).

Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: effect of nicotine treatment.

Acetylcholinesterase (AChE) is shown to promote deposition of beta-amyloid (Abeta) peptides and to enhance Abeta toxicity. Tg2576 (transgenic mice carrying the Swedish mutation of amyloid precursor protein, APPswe) mice and mice overexpressing human synaptic acetylcholinesterase (AChE-S) were crossed (hAChE-Tg//APPswe), to study the effects of brain Abeta, from 1 to 10 months of age, under the constant influence of AChE-S. The effect of nicotine treatment was also evaluated in these mice since we have previously shown that nicotine dramatically decreases Abeta levels in single transgenic APPswe mice.

[(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.

[(11)C]-PIB positron emission tomography ([(11)C]-PIB PET) is a sensitive marker of amyloid in Alzheimer's disease (AD), but its specificity has not been fully evaluated. Vascular amyloid-beta deposition is common in Parkinson's disease (PD) and alpha-synuclein, the major component of the Lewy bodies in PD, forms amyloid fibrils. We investigated five apparently cognitively normal PD patients with [(11)C]-PIB PET.

Vertebral fractures fixation with composite patch fibre reinforced adhesives.

Purpose: The aim is to investigate fixation of cervical vertebral fractures by patching it with a composite laminate of adhesive and fibres, in comparison with use of only adhesives.

Material And Methods: The composite fixation was tested on bonded roe deer vertebrae. 25 specimens were sawed in two halves, creating a generic fracture, and thereafter bonded.

In vivo amyloid imaging with PET in frontotemporal dementia.

Background: N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding.

Purpose: The aim of this study is to investigate PIB retention in FTD.

Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine.

In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo.

Amyloid imaging in Alzheimer's disease.

Purpose Of Review: This paper reviews the progress in developing amyloid imaging ligands to be used to measure amyloid in vivo in the brain of patients with Alzheimer's disease.

Recent Findings: Four radioligands, [18F] 1,1-dicyano-2-[6-(dimethylamino)-2-naphtalenyl] propene or 18F-FDDNP, N-methyl [11C] 2-(4'-methylaminophenyl)-6-hydroxy-benzothiasole or 11C-PIB, 4-N-methylamino-4'-hydroxystilbene [11C] or SB13 and 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole or 11C-BF-227, have so far been studied in Alzheimer's disease patients and age-matched healthy controls by PET. A robust difference was observed between PIB retention in mild patients and controls.

Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway.

The cholesterol 24-hydroxylase encoded by the gene CYP46 is expressed almost exclusively in central nervous system (CNS) neurons and catalyzes the formation of 24S-hydroxycholesterol (24S-OHC) from cholesterol. This conversion corresponds to a major pathway for excretion of excess cholesterol from the brain. There is a significant flux of another oxysterol, 27-hydroxycholesterol (27-OHC) from the circulation into the brain.

PET imaging of amyloid deposition in patients with mild cognitive impairment.

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.

The consequences of reducing expression of the alpha7 nicotinic receptor by RNA interference and of stimulating its activity with an alpha7 agonist in SH-SY5Y cells indicate that this receptor plays a neuroprotective role in connection with the pathogenesis of Alzheimer's disease.

In order to examine the neuroprotective effects of the alpha7 nicotinic receptor (nAChR) in relationship to the pathogenesis of Alzheimer's disease (AD), neuroblastoma (SH-SY5Y) cells were transfected with small interference RNAs (siRNAs) that targets specifically towards alpha7 nAChR or exposed to 20microM 3-[2,4-dimethoxybenzylidene] anabaseine (DMXB), a selective agonist of this same receptor. The levels of alpha7 nAChR mRNA and protein were measured by RT-PCR and Western blotting, respectively. The levels of the alpha-form of secreted amyloid precursor protein (alphaAPPs), total APP and the extracellular signal-regulated kinase 1/2 (ERK1/2) were also determined by Western blotting.

Postnatal upregulation of alpha4 and alpha3 nicotinic receptor subunits in the brain of alpha7 nicotinic receptor-deficient mice.

The nicotinic receptor subtypes are important for several physiological functions in brain and may therefore play a critical role in brain development. The alpha7 nicotinic receptors which have high Ca2+ permeability are important for cognitive, neuroprotective and trophic functions. In this study, the brain development and the expression of alpha4, alpha3, alpha7, alpha5 and beta2 nicotinic receptors were investigated in the brains of alpha7 deficient (alpha7 -/-), alpha7 heterozygous null (alpha7 +/-) and alpha7 wild-type (alpha7 +/+) mice from postnatal days (P) 7-84.

Effects of statins on alpha7 nicotinic receptor, cholinesterase and alpha-form of secreted amyloid precursor peptide in SH-SY5Y cells.

In order to reveal the neuroprotective effects of statins that could be of interest for the prevention and treatment of Alzheimer's disease (AD), we investigated the expression of nicotinic acetylcholine receptors (nAChRs) detected by RT-PCR, the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by colorimetric determination, and the levels of the alpha-form of secreted beta-amyloid precursor protein (alphaAPPs) by Western blotting in neuroblastoma (SH-SY5Y) cells exposed to lovastatin, atorvastatin, rosuvastatin and simvastatin, respectively. The results indicated that all statins studied, both lipophilic and hydrophilic, induced high expression of alpha7 nAChR, decreased cholinesterase activities, and increased alphaAPPs, which suggests that statins might play important neuroprotective roles in AD treatment.

PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD.

The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients' cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24mg/day) and 6 patients the placebo, and this was followed by 9 months' galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity ((11)C-PMP) and (11)C-nicotine binding.

Beta-amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress.

Calcineurin is an abundant cytosolic protein that is implicated in the modulation of glutamate release. Here we show that the expression level of this enzyme is reduced in primary neuronal cultures treated with beta-amyloid. Parallel experiments in ETNA cell lines expressing SOD1 suggested that the effect of beta-amyloid on calcineurin expression is mediated by oxidative stress.

Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET.

Rationale: Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer's disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD.

Retinoic acid and nerve growth factor induce differential regulation of nicotinic acetylcholine receptor subunit expression in SN56 cells.

Retinoic acid (RA) and nerve growth factor (NGF) have multiple functions in the regulation of neuronal development. In the present study, we characterized the expression of different nicotinic acetylcholine receptor (nAChR) subtypes in the cholinergic SN56 cell line and investigated the roles of RA and NGF in the expression of choline acetyltransferase (ChAT) and different nAChR subtypes. The nAChR agonist [(3)H]epibatidine was bound to two sites, with apparent affinities of 13 and 380 pM.

Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients.