Biomedical subjects

Fusheng Yang

Publications and source records attributed to Fusheng Yang.

At least 19 recordsLinked to original sources

PubMed2006

Antibodies against beta-amyloid reduce Abeta oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro.

Although active and passive immunization against the beta-amyloid peptide (Abeta) of amyloid plaque-bearing transgenic mice markedly reduces amyloid plaque deposition and improves cognition, the mechanisms of neuroprotection and impact on toxic oligomer species are not understood. We demonstrate that compared to control IgG2b, passive immunization with intracerebroventricular (icv) anti-Abeta (1-15) antibody into the AD HuAPPsw (Tg2576) transgenic mouse model reduced specific oligomeric forms of Abeta, including the dodecamers that correlate with cognitive decline. Interestingly, the reduction of soluble Abeta oligomers, but not insoluble Abeta, significantly correlated with reduced tau phosphorylation by glycogen synthase kinase-3beta (GSK-3beta), a major tau kinase implicated previously in mediating Abeta toxicity. A conformationally-directed antibody against amyloid oligomers (larger than tetramer) also reduced Abeta oligomer-induced activation of GSK3beta and protected human neuronal SH-SY5Y cells from Abeta oligomer-induced neurotoxicity, supporting a role for Abeta oligomers in human tau kinase activation. These data suggest that antibodies that are highly specific for toxic oligomer subspecies may reduce toxicity via reduction of GSK-3beta, which could be an important strategy for Alzheimer's disease (AD) therapeutics.

Amyloid beta-Peptides↗

PubMed2006

Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease.

Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.

Actin Depolymerizing Factors↗

PubMed2005

Increased cholesterol in Abeta-positive nerve terminals from Alzheimer's disease cortex.

Synapse loss in Alzheimer's disease (AD) is poorly understood but evidence suggests it is a key pathological event. In order to precisely detect stable synaptic changes, we have developed methods for flow cytometry analysis of synaptosomes prepared from cryopreserved AD samples, and have previously shown that amyloid-beta (Abeta) accumulates in surviving presynaptic terminals in AD cortex. In the present experiments we have examined amyloid-containing terminals in more detail, first dual labeling synaptosomes from AD cortex for Abeta and a series of markers, and then using quadrant analysis to compare amyloid-positive and amyloid-negative terminals. Amyloid-positive synaptosomes were larger in size than amyloid-negatives (p<0.007), and significant increases were observed in mean fluorescence for the lipid raft markers cholesterol (27%; p<0.0005) and GM1 ganglioside (24%; p<0.005). SNAP-25 immunofluorescence was increased by 31% (p<0.0001) in amyloid-bearing terminals, consistent with a sprouting response to amyloid accumulation. These results suggest that Abeta accumulation in synaptic terminals may underly dysfunction prior to or independent of extracellular amyloid deposition.

Adaptation, Physiological↗

PubMed2005

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions.

Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.).

Alzheimer Disease↗

PubMed2005

An epileptic seizure prediction algorithm based on second-order complexity measure.

The quality of life of many epilepsy patients may be improved significantly if the occurrence of epileptic seizures can be successfully forecasted and clinical intervention, such as electrical stimulation or drug delivery, can then be used to suppress their emergence, or warn the patient of the forthcoming events. In this paper, a prediction algorithm based on the second-order complexity measure was proposed to predict the impending seizures. Through the analysis of long-term intracranial EEG recordings from two frontal lobe epilepsy patients, the results indicated that the sensitivity of prediction was 77.8% (14/18) and 66.7% (4/6) and the number of false warnings was 3 and 2 for the two patients, respectively. Because only the information of past seizures was utilized to predict the current seizure and the computation load was low, the prediction algorithm could possibly be applied to clinical practice.

Adolescent↗

PubMed2005

A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.

Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Abeta by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Abeta42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Abeta (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both alpha- and beta-APP C-terminal fragment products and full-length APP. BACE1 (beta-secretase activity of the beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against beta-amyloid production, accumulation, and potential downstream toxicity.

Administration, Oral↗

PubMed2005

Ibuprofen suppresses interleukin-1beta induction of pro-amyloidogenic alpha1-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer's models.

Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Abeta) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Abeta production has not been ruled out. We show that ibuprofen reduced Abeta brain levels in rats from exogenously infused Abeta in the absence of altered Abeta production. To determine whether ibuprofen inhibits pro-amyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Abeta and inflammation-related molecules alpha1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor gamma) (PPARgamma) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1beta, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Abeta42 production, these observations suggest that ibuprofen reduction of Abeta pathology may not be mediated by altered Abeta42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1beta and its downstream target ACT).

Acute-Phase Proteins↗

PubMed2005

Standardized shrinking LORETA-FOCUSS (SSLOFO): a new algorithm for spatio-temporal EEG source reconstruction.

This paper presents a new algorithm called Standardized Shrinking LORETA-FOCUSS (SSLOFO) for solving the electroencephalogram (EEG) inverse problem. Multiple techniques are combined in a single procedure to robustly reconstruct the underlying source distribution with high spatial resolution. This algorithm uses a recursive process which takes the smooth estimate of sLORETA as initialization and then employs the re-weighted minimum norm introduced by FOCUSS. An important technique called standardization is involved in the recursive process to enhance the localization ability. The algorithm is further improved by automatically adjusting the source space according to the estimate of the previous step, and by the inclusion of temporal information. Simulation studies are carried out on both spherical and realistic head models. The algorithm achieves very good localization ability on noise-free data. It is capable of recovering complex source configurations with arbitrary shapes and can produce high quality images of extended source distributions. We also characterized the performance with noisy data in a realistic head model. An important feature of this algorithm is that the temporal waveforms are clearly reconstructed, even for closely spaced sources. This provides a convenient way to estimate neural dynamics directly from the cortical sources.

Action Potentials↗

PubMed2005

Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease.

Epidemiological data indicate that low n-3 polyunsaturated fatty acids (PFA) intake is a readily manipulated dietary risk factor for Alzheimer's disease (AD). Studies in animals confirm the deleterious effect of n-3 PFA depletion on cognition and on dendritic scaffold proteins. Here, we show that in transgenic mice overexpressing the human AD gene APPswe (Tg2576), safflower oil-induced n-3 PFA deficiency caused a decrease in N-methyl-D-aspartate (NMDA) receptor subunits, NR2A and NR2B, in the cortex and hippocampus with no loss of the presynaptic markers, synaptophysin and synaptosomal-associated protein 25 (SNAP-25). n-3 PFA depletion also decreased the NR1 subunit in the hippocampus and Ca2+/calmodulin-dependent protein kinase (CaMKII) in the cortex of Tg2576 mice. These effects of dietary n-3 PFA deficiency were greatly amplified in Tg2576 mice compared to nontransgenic mice. Loss of the NR2B receptor subunit was not explained by changes in mRNA expression, but correlated with p85alpha phosphatidylinositol 3-kinase levels. Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice. This effect was minimal in nontransgenic mice suggesting that n-3 PFA depletion potentiated caspase activation in the Tg2576 mouse model of AD. Dietary supplementation with docosahexaenoic acid (DHA; 22 : 6n-3) partly protected from NMDA receptor subunit loss and accumulation of fodrin and gelsolin fragments but fully prevented CaMKII decrease. The marked effect of dietary n-3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk.

Alkaloids↗

PubMed2004

Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo.

Alzheimer's disease (AD) involves amyloid beta (Abeta) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential Abeta binding, we investigated whether its efficacy in AD models could be explained by effects on Abeta aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC(50) = 0.8 microM) as well as disaggregated fibrillar Abeta40 (IC(50) = 1 microM), indicating favorable stoichiometry for inhibition. Curcumin was a better Abeta40 aggregation inhibitor than ibuprofen and naproxen, and prevented Abeta42 oligomer formation and toxicity between 0.1 and 1.0 microM. Under EM, curcumin decreased dose dependently Abeta fibril formation beginning with 0.125 microM. The effects of curcumin did not depend on Abeta sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.

Alzheimer Disease↗

PubMed2004

Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.

Actins↗

PubMed2004

Enrichment of presynaptic and postsynaptic markers by size-based gating analysis of synaptosome preparations from rat and human cortex.

BACKGROUND: Synapse regions in the brain are difficult to isolate and study; resealed nerve terminals (synaptosomes) are a widely used in vitro system for the study of neurotransmission, but nonsynaptosomal elements in the homogenate complicate data interpretation. With the goal of quantitative analysis of pathways leading to synapse loss in neurodegenerative disease, we have developed a method that allows focus on the intact synaptosomes within a crude synaptosomal preparation by gating the largest particles based on forward angle light scatter (FSC). METHODS: Crude synaptosomal fractions (P-2) were prepared and labeled with a viability dye (calcein AM), a presynaptic marker (SNAP-25), and a postsynaptic marker (PSD-95). Forward scatter gates based on size standards were drawn to identify the large population (1.4-4.5 microm), and the enrichment of each marker was quantified in preparations from fresh rat homogenates and from cryopreserved human cortex. RESULTS: Gating on forward scatter resulted in an increase that was highly significant (P < 0.001) for all three markers examined. The calcein-AM-positive fraction in the large synaptosomes was 98% +/- 0.8, and 75% +/- 9.8 for rat and human, respectively. Of large particles, 90% +/- 2.7 in rat and 82% +/- 2.6 in human were positive for SNAP-25, indicating a relatively pure population of intact synaptosomes. A total of 76% +/- 2.9 of the large particles were positive for PSD-95 in rat. This compared to 36% +/- 3.0 in human tissue, and indicates that both presynaptic and postsynaptic elements may be analyzed with this methodology. CONCLUSIONS: Most nonsynaptosomal elements can be excluded and the intact subpopulation of interest within the P-2 can be identified based on size. Size-based gating analysis provides a simple and cost-effective method to monitor fluorescence changes in synapse regions.

Aged↗

PubMed2004

Mu rhythm-based cursor control: an offline analysis.

OBJECTIVE: To classify the EEG data recorded in mu rhythm-based cursor control experiments with 4 possible choices. METHODS: The algorithm included preprocessing, feature extraction, and classification. Two spatial filters, common average reference and common spatial subspace decomposition, were used in preprocessing to improve the signal-to-noise ratio, and then two features were extracted based on the power spectrum and the time course of the mu rhythm respectively. A Fisher ratio was defined to select channels in feature extraction. A 2-dimensional linear classifier was trained for final classification. RESULTS: Two types of classifiers were trained for the training dataset. The uniform classifier gave a classification accuracy of 76.4%, and the classifier trained by leave-one-out method gave a classification accuracy of 74.4%, both higher than the online accuracy 69.5%. The uniform classifier was applied to the test dataset and the classification accuracy was 65.9%, lower than the online accuracy 73.2%. CONCLUSIONS: Spatial filtering can give a notable improvement in classification accuracy. The time course of the mu rhythm, as well as the power of the mu rhythm, shows difference between the 4 targets, and can contribute to the classification. SIGNIFICANCE: The spatial filtering, feature extraction and channel selection methods in the algorithm will provide some practical suggestions for further study on the mu rhythm-based brain-computer interface.

Algorithms↗

PubMed2004

Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence.

In an effort to examine changes that precede synapse loss, we have measured amyloid-beta and a series of damage markers in the synaptic compartment of Alzheimer's disease (AD) cases. Because localization of events to the terminal region in neurons is problematic with conventional methods, we prepared synaptosomes from samples of cryopreserved human association cortex, and immunolabeled terminals with a procedure for intracellular antigens. Fluorescence was quantified using flow cytometry. The viability dye calcein AM was unchanged in AD terminals compared to controls, and the fraction of large synaptosome particles did not change, although a striking loss of large terminals was observed in some AD cases. The percent positive fraction for a series of pre- and postsynaptic markers was not affected by AD in this cohort. However, the amyloid-beta-positive fraction increased from 16 to 27% (P < 0.02) in terminals from AD cortex. The expression level on a per-terminal basis is indicated in this assay by fluorescence (relative fluorescence units). The fluorescence of presynaptic markers did not change in AD terminals, but PSD-95 fluorescence was decreased by 19% (P < 0.03). Amyloid-beta fluorescence was increased by 132% (P < 0.01), and glial fibrillary acidic protein labeling by 31% (P < 0.01). These results suggest that synapse-associated amyloid-beta is prominent in regions relatively unaffected by AD lesions, and that amyloid accumulation in surviving terminals is accompanied by gliosis and alteration in the postsynaptic structure.

Aged↗

PubMed2004

BCI Competition 2003--Data set IV: an algorithm based on CSSD and FDA for classifying single-trial EEG.

This paper presents an algorithm for classifying single-trial electroencephalogram (EEG) during the preparation of self-paced tapping. It combines common spatial subspace decomposition with Fisher discriminant analysis to extract features from multichannel EEG. Three features are obtained based on Bereitschaftspotential and event-related desynchronization. Finally, a perceptron neural network is trained as the classifier. This algorithm was applied to the data set (self-paced 1s) of "BCI Competition 2003" with a classification accuracy of 84% on the test set.

Algorithms↗

PubMed2004

BCI Competition 2003--Data set IIb: enhancing P300 wave detection using ICA-based subspace projections for BCI applications.

An algorithm based on independent component analysis (ICA) is introduced for P300 detection. After ICA decomposition, P300-related independent components are selected according to the a priori knowledge of P300 spatio-temporal pattern, and clear P300 peak is reconstructed by back projection of ICA. Applied to the dataset IIb of BCI Competition 2003, the algorithm achieved an accuracy of 100% in P300 detection within five repetitions.

Algorithms↗

PubMed2004

A recursive algorithm for the three-dimensional imaging of brain electric activity: Shrinking LORETA-FOCUSS.

Estimation of intracranial electric activity from the scalp electroencephalogram (EEG) requires a solution to the EEG inverse problem, which is known as an ill-conditioned problem. In order to yield a unique solution, weighted minimum norm least square (MNLS) inverse methods are generally used. This paper proposes a recursive algorithm, termed Shrinking LORETA-FOCUSS, which combines and expands upon the central features of two well-known weighted MNLS methods: LORETA and FOCUSS. This recursive algorithm makes iterative adjustments to the solution space as well as the weighting matrix, thereby dramatically reducing the computation load, and increasing local source resolution. Simulations are conducted on a 3-shell spherical head model registered to the Talairach human brain atlas. A comparative study of four different inverse methods, standard Weighted Minimum Norm, L1-norm, LORETA-FOCUSS and Shrinking LORETA-FOCUSS are presented. The results demonstrate that Shrinking LORETA-FOCUSS is able to reconstruct a three-dimensional source distribution with smaller localization and energy errors compared to the other methods.

Algorithms↗

PubMed2004

NSAID and antioxidant prevention of Alzheimer's disease: lessons from in vitro and animal models.

Both oxidative damage and inflammation are elevated in brains of Alzheimer's disease (AD) patients, but their pathogenic significance remains unclear. The reduced AD risk associated with high intake of both nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants suggests causal roles, but clinical trials in AD patients have yielded only limited or negative results. To test the potential efficacy and mechanisms of candidate approaches, we have explored conventional and unconventional NSAIDs, antioxidants, and combined NSAID/antioxidants in cell culture and animal models for AD (including aging APPsw transgenic mice and soluble Abeta rodent infusion models). The conventional NSAID ibuprofen has the strongest epidemiological support. At sustainable doses designed to mimic protective consumption in the epidemiology, ibuprofen reduces amyloid accumulation but suppresses a surprisingly limited subset of inflammatory markers in APPsw transgenic mice. Both Ab production (APP, beta- and gamma-secretases) and post-production pathways (those affecting Abeta aggregation or clearance: e.g., IL-1 or alpha1ACT) are potentially involved in ibuprofen and other NSAID anti-AD activities. The post-production pathways are predictably shared with other seemingly protective NSAIDs, including naproxen that do not lower Abeta42 in vitro. Using clinically feasible dosing, brain levels of NSAIDs appear too low to implicate a number of pharmacological dose targets that have been demonstrated in vitro. Ibuprofen did not suppress microglial markers related to phagocytosis. The putative anti-inflammatory omega-3 fatty acid DHA had a profound impact on pathogenesis but did not lower inflammation, while vitamin E was surprisingly ineffective in reducing oxidative damage or amyloid in the aged APPsw mouse. In contrast, the unconventional NSAID/antioxidant curcumin was effective, lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid deposition. Curcumin proved to be immunomodulatory, simultaneously inhibiting cytokine and microglial activation indices related to neurotoxicity, but increasing an index of phagocytosis. Curcumin directly targeted Abeta and was also effective in other models, warranting further preclinical and clinical exploration.

Alzheimer Disease↗