Alzheimer Disease: Yan Y

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.

Liu XQ, Liu XQ, Jiang P, Huang H, Yan Y. · Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #19087670 No free full text.

Abstract: OBJECTIVE: To investigate the plasma levels of endogenous hydrogen sulfide (H2S), a gasotransmitter, and homocysteine (Hcy) in patients with Alzheimer's disease (AD), vascular dementia (VD), and cerebrovascular disease (CVD) and their role in the pathogenesis of AD and VD. METHODS: 31 AD patients, 28 VD patients, 20 CVD patients , and 23 normal controls (NC group) underwent examination of plasma concentrations of H2S and Hcy, mini mental state examination (MMSE), activity of daily living scale (ADL), Hachinski ischemic score (HIS) , and Hamilton's depression scale (HRSD). The severity of AD and VD was evaluated according to the global deterioration scale (GDS). RESULTS: (1) The plasma H2S levels of the AD, VD, and CVD patients were (34 +/- 7), (36 +/- 5), and (37 +/- 7) micromol/L respectively, all significantly lower than that of the NC group [(45 +/- 7) micromol/L, all P < 0.01]. However, there were no significant differences in the plasma H2S level among the AD, VD, and CVD patients (all P > 0.05). The plasma H2S concentration was negatively correlated the severity of AD. (2) The plasma Hcy levels of the AD, VD, and CVD patients were (14.0 +/- 3.0), (16.0 +/- 6.1), and (14.4 +/- 4.9) micromol/L respectively, all significantly higher than that of the NC group [(9.8 +/- 2.5) micromol/L, P < 0.01). However, there was no significant difference in the plasma Hcy level among these 3 groups (all P > 0.05). The plasma Hcy concentration was positively correlated with the severity of AD or VD. CONCLUSION: H2S and Hcy are both involved in the pathogenesis of AD, VD, and CVD, and its alteration in level may be associated with the severity of AD and VD.

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.

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.

Xiong C, Yu K, Gao F, Yan Y, Zhang Z. · Division of Biostatistics, Washington University in St Louis, MO 63110, USA. · Clin Trials. · Pubmed #16317808 No free full text.

Abstract: BACKGROUND: When the efficacy of a treatment in a randomized controlled trial is required for multiple primary endpoints, trial design and analysis differ from trial requiring efficacy in only one of the multiple endpoints. METHODS: We consider a two-arm clinical trial requiring efficacy analysis for multiple primary endpoints, formulating the appropriate null and alternative hypotheses for the test of treatment efficacy. We study the significance level/statistical power of an intersection-union test (IUT) in this situation. We compare IUT with the intuitive approach (selecting the maximum sample size over those obtained from testing individual primary endpoints one by one) for determination of sample size. RESULTS: The proposed IUT reserves the same Type I error rate as shared by all endpoint-specific tests. The statistical power of the proposed IUT is no more than the minimum from the individual tests. The maximum sample size from multiple endpoint-specific tests is often inadequate for the test of treatment efficacy, especially when the standardized effect sizes are similar. Finally, the IUT can be applied to Alzheimer's disease treatment trials in which two primary endpoints are typically used. CONCLUSIONS: The IUT is a valid method for use in the design and analysis of clinical trials requiring efficacy at multiple primary endpoints.

Huang P, Miao S, Fan H, Sheng Q, Yan Y, Wang L, Koide SS. · National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Faculty of Basic Medicine, Peking Union Medical College, 5 Dong Dan 3 Tiao, Beijing 100005. · Mol Hum Reprod. · Pubmed #11101689 links to  free full text

Abstract: The YWK-II cDNA, RSD-2, encoding a sperm membrane protein was isolated from a rat testis cDNA expression library. Using the RSD-2 insert in combination with rapid amplification of cDNA ends (RACE), the corresponding human gene was isolated from a human testis cDNA expression library. The human testis cDNA, HSD-2, is 3654 bp in length and contains an open reading frame of 763 codons. Hydropathicity analysis showed that the deduced polypeptide is a single strand transmembrane protein. The deduced polypeptide has partial homology with the amyloid precursor protein (APP) and high homology with the amyloid precursor homologue, APLP2/APPH. The YWK-II gene was mapped and assigned to human chromosome locus: 11q24-25. Northern blotting of various human tissue RNAs using the HSD-2 cDNA as a probe showed that the gene is transcribed ubiquitously. The cytoplasmic domain of HSD-2 was expressed in Escherichia coli. In-vitro studies showed that the recombinant polypeptide bound to a GTP-binding protein (G(o)) and was phosphorylated by protein kinase C and cdc2 kinase. In mammalian F11 cells, the recombinant polypeptide was found to be coupled to G(o). Thus, the YWK-II component has the characteristics of a G(o)-coupled receptor and may be involved in G(o)-mediated signal transduction pathway. Protein kinase C and cdc2 kinase may regulate this pathway in spermatozoa by phosphorylating the cytoplasmic domain of the YWK-II component.