Alzheimer Disease: Wang C

Yan Y, Wang C. · Biology department, Rensselear Polytechnic Institute, Troy, NY 12180, USA. · Curr Alzheimer Res. · Pubmed #19075581 No free full text.

Abstract: It is widely accepted that Abeta42 aggregation is a central event in the pathogenesis of Alzheimer's disease. Abeta42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. There are a number of physiological molecules that can protect Abeta42 from aggregation. Promoting such protective molecules and mechanisms against Abeta42 aggregation may be a novel direction in AD drug discovery. One of the most striking protective molecules is none other than Abeta40, which inhibits Abeta42 aggregation in a specific and dosage dependent manner. Abeta40 is a critical, built-in mechanism against Abeta42 aggregation. A number of other molecules and mechanisms also inhibit Abeta42 aggregation, such as heat shock proteins, L-PGDS, heme and methionine oxidation. The relevance of these protective mechanisms to AD pathogenesis and intervention is discussed.

deToledo-Morrell L, Stoub TR, Wang C. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Prog Brain Res. · Pubmed #17765748 No free full text.

Abstract: Quantitative imaging techniques allow the in vivo investigation of age and disease related changes in the brain and their relation to cognitive function. In this chapter we review imaging evidence indicating that the entorhinal cortex and hippocampus show atrophy very early in Alzheimer's disease (AD) and in individuals who are at risk of developing AD compared to age appropriate controls. Furthermore, the extent and rate of atrophy of the entorhinal cortex, a brain region pathologically involved very early in the disease process, can predict who among the elderly will develop AD. Techniques that assess the integrity of white matter further demonstrate that alterations in the parahippocampal white matter in the region that includes the perforant path could partially disconnect the dentate gyrus and other hippocampal subfields from incoming sensory information. Such partial disconnection and degradation in transmission of sensory information in people at risk of AD and in patients with very mild AD could contribute to the memory dysfunction associated with the early stages of the disease.

Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. · Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA. · Nat Med. · Pubmed #18806802 No free full text.

Abstract: Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.

Yan Y, McCallum SA, Wang C. · Biology Department, Center for Biotechnology and Interdisciplinary Studies, Rensselear Polytechnic Institute, Troy, New York 12180, USA. · J Am Chem Soc. · Pubmed #18376837 No free full text.

Abstract: Oxidizing a single M35 residue of Abeta leads to delayed aggregation and reduced toxicity. To understand the molecular mechanism of this effect, we examined the structural and dynamical consequences of M35 oxidation. We found the mobility of the C-terminal residues of Abeta42 is greatly enhanced upon M35 oxidation. In contrast, methyl groups in the central hydrophobic cluster become less flexible. Taken together, we conclude that Abeta42ox undergoes Abeta40-like structural and dynamical changes, which contribute to its reduced aggregation and toxicity.

Jiang LF, Yao TM, Zhu ZL, Wang C, Ji LN. · Department of Chemistry, Tongji University, Shanghai 200092, China. · Biochim Biophys Acta. · Pubmed #17920001 No free full text.

Abstract: Environmental exposure to some heavy metals such as cadmium appears to be a risk factor for Alzheimer's disease (AD), however, definite mechanism of their toxicity in AD remains to be elucidated. Previous studies largely focused on the metal ions binding to beta-amyloid, however, very few papers concerned the interaction between tau and metal ions. For the first time, we investigated the impacts of Cd(II) on the conformation and self-aggregation of Alzheimer's tau peptide R3, corresponding to the third repeat of microtubule-binding domain. The initial state of R3 was proven to be dimeric linked by intermolecular disulfide bond, in the non-reducing buffer (Tris-HCl buffer pH7.5, containing no reducing reagent). In this paper, we show that Cd(II) can accelerate heparin-induced aggregation of R3 or independently induce the aggregation of R3, as monitored by ThS fluorescence. In the presence of Cd(II), the resulting R3 filaments became much smaller, as revealed by electron microscopy. Binding to the Cd(II) ion, the dimeric R3 partially lost its random coil, and converted to alpha-helix structure, as revealed by CD and Raman spectrum. Stoichiometric analysis of CD signal against the ratio of [Cd(II)]/[R3] suggested that the coordination intermediate consisted of two R3 dimers binding to a central cadmium ion. As the seed, the coordination intermediate could extensively accelerate the self-aggregation of R3 via promoting the nucleation step. On the other hand, gain in alpha-helix structure on the peptide chain, by coordinating with Cd(II), could be a critical role to promote self-aggregation, as revealed by Raman spectrum. These results provide a further insight into the mechanism of tau filament formation and emphasize the possible involvement of Cd(II) in the pathogenesis of AD.

Zheng H, Wei DQ, Zhang R, Wang C, Wei H, Chou KC. · College of Life Sciences and Technology, Shanghai Jiaotong University, Minhang District, Shanghai, China. · Med Chem. · Pubmed #17897076 No free full text.

Abstract: To find new drug candidates for treating Alzheimer's disease, we used the similarity search technique and GTS-21 as a template to search the Traditional Chinese Medicines Database. The high-score molecules thus obtained were compared with the template through the flexible alignment. Those molecules which had good alignment with GTS-21 were selected for conducting the docking studies aimed at the alpha7 nicotinic acetylcholine receptor. The CHARMM22 force field was taken to compute the partial charge and the TABU search was adopted to operate the docking process. The docking results thus obtained were used to compare with that of GTS-21. Those molecules which had better docking results than that of GTS-21 were singled out for further consideration. Finally, it was found through an in-depth structural analysis that Mol 7235 might be a promising candidate for further modification by experiments to make it become an effective drug for treating Alzheimer's disease.

Yin YI, Bassit B, Zhu L, Yang X, Wang C, Li YM. · Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 and Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180. · J Biol Chem. · Pubmed #17556361 links to  free full text

Abstract: Mutation of the amyloid precursor protein (APP), presenilin-1, or presenilin-2 results in the development of early onset autosomal dominant forms of Alzheimer disease (AD). These mutations lead to an increased Abeta42/Abeta40 ratio that correlates with the onset of disease. However, it remains unknown how these mutations affect gamma-secretase, a protease that generates the termini of Abeta40 and Abeta42. Here we have determined the reaction mechanism of gamma-secretase with wild type and three mutated APP substrates. Our findings indicate that despite the overall outcome of an increased Abeta42/Abeta40 ratio, these mutations each display rather distinct reactivity to gamma-secretase. Intriguingly, we found that the ratio of Abeta42/Abeta40 is variable with substrate concentration; increased substrate concentrations result in higher ratios of Abeta42/Abeta40. Moreover, we demonstrated that reduction of gamma-secretase substrate concentration by BACE1 inhibition in cells decreased the Abeta42/Abeta40 ratio. This study indicates that biological factors affecting targets such as BACE1 and APP, which ultimately cause an increased concentration of gamma-secretase substrate, can augment the Abeta42/Abeta40 ratio and may play a causative role in sporadic AD. Therefore, strategies lowering the Abeta42/Abeta40 ratio through partial reduction of gamma-secretase substrate production may introduce a practical therapeutic modality for treatment of AD.

Yan Y, Wang C. · Center for Biotechnology and Interdisciplinary Studies, Biology Department, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. · J Mol Biol. · Pubmed #17481654 No free full text.

Abstract: Abeta40 and Abeta42 are the predominant Abeta species in the human body. Toxic Abeta42 oligomers and fibrils are believed to play a key role in causing Alzheimer's disease (AD). However, the role of Abeta40 in AD pathogenesis is not well established. Emerging evidence indicates a protective role for Abeta40 in AD pathogenesis. Although Abeta40 is known to inhibit Abeta42 fibril formation, it is not clear whether the inhibition acts on the non-toxic monomer or acts on the toxic Abeta42 oligomers. In contrast to conventional methods that detect the appearance of fibrils, in our study Abeta42 aggregation was monitored by the decreasing NMR signals from Abeta42 monomers. In addition, differential NMR isotope labelling enabled the selective observation of Abeta42 aggregation in a mixture of Abeta42 and Abeta40. We found Abeta40 monomers inhibit the aggregation of non-toxic Abeta42 monomers, in an Abeta42/Abeta40 ratio-dependent manner. NMR titration revealed that Abeta40 monomers bind to Abeta42 aggregates with higher affinity than Abeta42 monomers. Abeta40 can also release Abeta42 monomers from Abeta42 aggregates. Thus, Abeta40 likely protects Abeta42 monomers by competing for the binding sites on pre-existing Abeta42 aggregates. Combining our data with growing evidence from transgenic mice and human genetics, we propose that Abeta40 plays a critical, protective role in Alzheimer's by inhibiting the aggregation of Abeta42 monomer. Abeta40 itself, a peptide already present in the human body, may therefore be useful for AD prevention and therapy.

Sgourakis NG, Yan Y, McCallum SA, Wang C, Garcia AE. · Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. · J Mol Biol. · Pubmed #17397862 links to  free full text

Abstract: The role of peptides Abeta40 and Abeta42 in the early pathogenesis of Alzheimer's disease (AD) is frequently emphasized in the literature. It is known that Abeta42 is more prone to aggregation than Abeta40, even though they differ in only two (IA) amino acid residues at the C-terminal end. A direct comparison of the ensembles of conformations adopted by the monomers in solution has been limited by the inherent flexibility of the unfolded peptides. Here, we characterize the conformations of Abeta40 and Abeta42 in water by using a combination of molecular dynamics (MD) and measured scalar (3)J(HNHalpha) data from NMR experiments. We perform replica exchange MD (REMD) simulations and find that classical forcefields reproduce the NMR data quantitatively when the sampling is extended to the microseconds time-scale. Using the quantitative agreement of the NMR data as a validation of the model, we proceed to compare the conformational ensembles of the Abeta40 and Abeta42 peptide monomers. Our analysis confirms the existence of structured regions within the otherwise flexible Abeta peptides. We find that the C terminus of Abeta42 is more structured than that of Abeta40. The formation of a beta-hairpin in the sequence (31)IIGLMVGGVVIA involving short strands at residues 31-34 and 38-41 (in bold) reduces the C-terminal flexibility of the Abeta42 peptide and may be responsible for the higher propensity of this peptide to form amyloids.

Wang C, Wilson WA, Moore SD, Mace BE, Maeda N, Schmechel DE, Sullivan PM. · Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. · Neurobiol Dis. · Pubmed #15686968 No free full text.

Abstract: The human APOE*4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE*4 carriers. We examined neurons in the lateral amygdala of young apolipoprotein (apo) E3 and apoE4 targeted replacement (TR) mice for changes in synaptic integrity. ApoE4 mice displayed significantly reduced excitatory synaptic transmission and dendritic arborization. Despite these changes there were no signs of gliosis, amyloid deposition or neurofibrillary tangles in these mice. To our knowledge, this is the first study to suggest that cognitive deficits in APOE*4 carriers are due to inherent defects in synaptic function that appear prior to any age-dependent markers of neuropathology.

Wang C, Gonzalez R, Merajver SD. · Department of Health Behavior and Health Education, School of Public Health, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109-2029, USA. · Soc Sci Med. · Pubmed #14759687 No free full text.

Abstract: With the recent completion of the sequencing of the Human Genome, genetic testing will increasingly become available for a greater number of medical conditions, many of which are those that manifest in adulthood (e.g., various cancers, cardiovascular disease, diabetes) or for which little or no treatments are available (e.g., Alzheimer disease). Genetic services, defined here as those relating to genetic testing and counseling, will be with helping more individuals deal with medical information that affects their health directly, as opposed to affecting primarily the health of their offspring. This paper reviews the existing research in the genetic testing and counseling literature and presents an evaluation framework outlining the intended outcomes of genetic services. The purpose of this framework is to provide an overview of the potential outcomes of these services and highlight constructs for future research in this area. In addition, other issues that will affect the assessment of genetic services are raised, using examples from the existing literature. Ultimately, the goal of this paper is to highlight and suggest directions researchers can take to produce the information needed to guide genetic testing and counseling practice. Moreover, as genetic knowledge is increasingly applied towards the prevention and treatment of various common, chronic disease conditions, genetic information will have implications for providers outside of the traditional medical genetics realm, such as primary care providers and public health practitioners. A better understanding of the outcomes of genetic testing and counseling will provide a basis from which to ensure an appropriate application of genetic information by all those who eventually provide care and "genetic" services.

Wang Z, Zhou C, Wang C, Wan L, Fang X, Bai C. · The Center for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, PR China. · Ultramicroscopy. · Pubmed #12801659 No free full text.

Abstract: Atomic force microscopy (AFM) and scanning tunneling microscopy (STM) have been employed in situ and ex situ to directly study the aggregation of beta-amyloid(1-42) (Abeta42) peptide on hydrophobic graphite.From in situ AFM images, Abeta42 peptides were seen to aggregate into the sheets that preferred to three orientations with characteristic 3-fold symmetry (Proc. Natl. Acad. Sci. USA 96 (1999) 3688). The sheets were formed by parallel narrow lines with a height of 0.8-1.0nm and a width of 12-14nm. The narrow lines looked like beaded chains and have a right-handed axial periodicity.The high-resolution ex situ AFM and STM images showed that some fibrils of beta-amyloid had a characteristic domain texture, indicating they were formed through the association of protofibrils and monomers. The fibril containing lateral associated filaments that exhibited right-handed twist was clearly observed in the STM image.These results provide important clues to study the detailed structure of beta-amyloid aggregates and the mechanism of the Abeta fibrils formation on hydrophobic surface.