Alzheimer Disease: Zhang M

Zhang M. · Department of Biology, Synta Pharmaceuticals, 125 Hartwell Avenue, Lexington, MA 02421, USA. · Front Biosci. · Pubmed #18508646 No free full text.

Abstract: Extensive research has been carried out to elucidate the mechanism of neurodegenerative diseases, with special emphasis on lysosomal storage disease (LSD) and Alzheimer's disease (AD). Studies have outlined complicated profiles in both types of disorders for the role of endocytosis in disease pathogenesis and progression. Recent discoveries relating endocytosis to the pathological origin and therapeutic strategy of the diseases have yet to be addressed. In this review, I attempt to demonstrate a comprehensive analysis on the endocytic mechanism of the disease. I propose that LSD could be classified as a late endosomal trafficking disorder. I also highlight that the most critical cellular event in AD--the producing, processing, and trafficking of Abeta42 peptide--dynamically involves the entire endocytic system. I further analyze pipeline drug targets, summarize the development status of current new drugs, share thoughts on potential therapeutic strategies, and reveal that many such strategies are in close association with endocytosis. I emphasize that thoroughly understanding pathologically-relevant endocytic events is the key factor in speeding up discovery and development of novel drugs.

Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, Atchison K, Chlenov M, Cole DC, Comery T, Diamantidis G, Ellingboe J, Fan K, Galante R, Gonzales C, Ho DM, Hoke ME, Hu Y, Huryn D, Jain U, Jin M, Kremer K, Kubrak D, Lin M, Lu P, Magolda R, Martone R, Moore W, Oganesian A, Pangalos MN, Porte A, Reinhart P, Resnick L, Riddell DR, Sonnenberg-Reines J, Stock JR, Sun SC, Wagner E, Wang T, Woller K, Xu Z, Zaleska MM, Zeldis J, Zhang M, Zhou H, Jacobsen JS. · Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. · J Med Chem. · Pubmed #19012391 No free full text.

Abstract: SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Niu YY, Yang LM, Deng KM, Yao JH, Zhu L, Chen CY, Zhang M, Zhou JE, Shen TX, Chen HZ, Lu Y. · Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. · Bioorg Med Chem Lett. · Pubmed #17289384 No free full text.

Abstract: Muscarinic M2 receptor antagonists with high subtype selectivity (M2/M1) will decrease the toxicity in central nervous system in treatment of AD. The exploration of quantitative structure-selectivity relationship (QSSR) to muscarinic M2 receptor antagonists will provide design information for drug with fewer side effects. In this paper, CoMFA models of pK(i)(M1), pK(i)(M2) and p[K(i)(M2)/K(i)(M1)] (pK(i)(M2)-pK(i)(M1)) were used to study the subtype selectivity (M2/M1) of piperidinyl piperidine derivatives as muscarinic M2 subtype receptor antagonists. The parameters of the three models are: 0.633, 0.636 and 0.726 for cross-validated r(2) (r(cv)(2)), 0.109, 0.204 and 0.09 for the Standard error of estimate (SD), respectively. The results show the model of p[K(i)(M2)/K(i)(M1)] is the best one for design of piperidinyl piperidine derivatives as muscarinic antagonists with high subtype selectivity (M2/M1).

Cao Q, Jiang K, Liu Y, Zhang M, Xiao S, Zuo C, Huang H. · Department of Psychiatry, Huashan Hospital, Fudan University, Shanghai 200030, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #12667368 No free full text.

Abstract: OBJECTIVE: To study the feature of regional cerebral metabolism rate of glucose (rCMRglc) of Alzheimer's disease (AD) and mild cognitive impairment (MCI) by positron emission tomography (PET) and the relationship between MCI and AD. METHODS: 13 AD patients, 10 MCI patients and 10 health volunteers as a control group (HC) were underwent 18F-fluoro deoxyglucose (18F-FDG)-PET scanning. RESULTS: (1) There was lightly decreasing of radioactivity of temporal lobe and parietal lobe in HC group, a little severer decrease in MCI group, markedly decrease of radioactivity of temporal lobe, parietal lobe and frontal lobe in AD group examined by naked-eye. (2) The rCMRglc of many parts of brain such as frontal lobe, including superior, middle and inferior frontal gyrus, orbital gyrus and rectus gyrus, temporal lobe, including superior, middle and inferior temporal gyrus, parietal lobe, including superior parietal lobe, supramarginal gyrus and angular gyrus, limbic system, including anterior cingulate gyrus, insular lobe, basal ganglions, including thalamus, caudate nucleus and amygdaloid nucleus decreased significantly in AD group, compared to MCI and HC groups (p < 0.05 to p < 0.001). (3) The rCMRglc of many parts of brain such as frontal lobe, temporal lobe, parietal lobe, limbic system, and basal ganglions in MCI group was lower than that in HC group, but not significantly (p > 0.05). Only that of the left caudate nucleus in MCI decreased significantly compared to that in HC group (p < 0.05). CONCLUSION: Decreasing of rCMRglc of parietal lobe is sensitive in evaluating cognitive function, next one is temporal lobe, and then frontal lobe. The rCMRglc of frontal lobe, temporal lobe, parietal lobe, limbic system, and basal ganglions decreasing markedly indicates that global function decayed in AD patients. While the rCMRglc of those parts in MCI patients' brain decreases mildly. This indicates that MCI is the middle state of AD and HC. Decreasing of rCMRglc of the left caudate nucleus has a certain role in diagnosis of MCI.

Jiang S, Zhang M, Ren D, Tang G, Lin S, Qian Y, Zhang Y, Jiang K, Li F, Wang D. · Department of Genetics, Shanghai Institute of Mental Health, Shanghai 200030, People's Republic of China. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #12627474 No free full text.

Abstract: Previous studies have suggested the involvement of amyloid precursor protein (APP) in Alzheimer's disease (AD), as exons 16 and 17 of the APP gene mutations have been found in some familial AD patients. Furthermore, overexpression and deposition of the beta amyloid peptide, a proteolytic product of APP, have been considered as a pathological hallmark of Alzheimer's disease. Therefore, it is of particular interest to determine the expression of APP gene at the transcription level for better understanding of the roles of APP gene in AD pathogenesis. In this work, we employed the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to quantify APP mRNA transcripts in the peripheral mononuclear blood cells (PMBC) of 52 Alzheimer's patients, 28 vascular dementia (VD) patients, and 60 healthy elderly controls. The results showed that the amount (mean +/- SEM) of APP transcripts per microgram of total cDNA was 4.05 +/- 0.27, 2.73 +/- 0.33, and 2.59 +/- 0.27 amole in AD, VD, and healthy controls, respectively. There was a significant increase (P < 0.05) in the expression of APP mRNA transcripts in AD compared with that in VD or in healthy controls. Thus, our data indicated that variation of APP gene expression in PMBC might be a pathogenic source of Alzheimer's disease.

Tang G, Zhang M, Xie H, Jiang S, Wang Z, Xu L, Hao Y, Lin D, Lan H, Wang Y, Chen L, Ren D. · State Key Lab of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China. · Neurosci Lett. · Pubmed #12133586 No free full text.

Abstract: Several lines of evidence have revealed some overlapping pathologies in Alzheimer's disease (AD) and Parkinson's disease (PD). Although the alpha-2 macroglobulin gene (A2M) might be a risk factor of these two neurodegenerative diseases, conclusions from different studies have remained conflicting. Here we studied the role of A2M I1000 V polymorphism in both AD and PD in a Chinese Han population. We found that the A2M I/V genotype is associated with both AD (odds ratio (OR)=2.55, 95% confidential interval (95% CI): 1.20-5.43, attributable fraction (AF)=13.65%) and PD (OR=3.03, 95% CI: 1.30-7.02, AF=16.51%). After classifying according to the age of onset, this association is only detected in early-onset AD patients (OR=3.96, 95% CI: 1.28-12.26) and late-onset PD patients (OR=2.61, 95% CI: 0.97-7.09). Therefore, we conclude that in our samples, the A2M I/V genotype might be a susceptibility variant, even with minor effect, for both sporadic AD and PD.

Zhang X, Li C, Zhang M. · Shanghai Mental Health Center, Department of Psychiatry, Shanghai Second Medical University, Shanghai 200030. · Zhonghua Yi Xue Za Zhi. · Pubmed #11715471 No free full text.

Abstract: OBJECTIVE: To explore the relationship between psychosocial factor and risk of Alzheimer's disease(AD). METHODS: A cohort study of people 55 years and older was followed up 10 years after a baseline screening. 5,055 elderly subjects in a district of Shanghai were stratified clustering sampled from community. Information about psychosocial factors was collected in 1987. The clinical diagnoses of dementia and AD were made according to DSM-III-R and NINCDS-ADRDA criteria. 4,896 non-demented persons were followed in 1997. The incidence of AD was calculated and the relationship between the psychosocial factors and the AD was analyzed by Logistic model. RESULTS: 1,203 subjects were resurveyed in 1997 and among them 124 new cases of dementia including 81 cases of AD were identified. By computing the relative risk(RR) of psychosocial factors to the AD, many psychosocial factors were found to be correlated with AD including blue collar occupation, no job, no reading or writing, no taking community activities, no gardening in leisure, bad psychological feeling and lower education (RR > 1). The items with high PARP > 50% were not working, no job, retirement, no taking community activities, no reading or writing, blue collar occupation and no gardening in leisure. MMSE total score is a good predict for AD. CONCLUSION: Psychosocial factors play an important role in the development of Alzheimer's disease.

Tang G, Jiang S, Zhang M, Lin S, Qian Y, Wu X, Wang D, Jin T, Gu N. · Department of Genetics, Shanghai Institute of Mental Health, Shanghai, China. · Am J Med Genet. · Pubmed #10893483 No free full text.

Abstract: We investigated a common signal peptide polymorphism in the alpha 1-antichymotrypsin (ACT) gene in 125 sporadic Alzheimer disease (AD) patients and 141 healthy control subjects in Chinese Han population. We found no significant difference in the distribution of ACT polymorphism between AD cases and controls, and failed to detect any effects of ACT genotypes associated with AD. Thus, our data do not support the involvement of ACT polymorphism in the risk of AD in Chinese Han population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:133-135, 2000.

Tang G, Jiang S, Gu N, Jin T, Lin S, Qian Y, Wang D, Zhang M. · Shanghai Institute of Mental Health. Shanghai, 200030, P. R. China. · Zhonghua Yi Xue Yi Chuan Xue Za Zhi. · Pubmed #10194255 No free full text.

Abstract: OBJECTIVE: To detect the relation between alpha1-antichymotrpsin(AACT)gene polymorphism and epsilon4 allele of apolipoprotein E (ApoE) gene in Alzheimer disease (AD) in Chinese. METHODS: The gene polymorphisms of ApoE and AACT were genotyped in 125 AD cases and 140 controls with PCR methods and RFLP typing. Then the association between AACT polymorphism and ApoE epsilon4 was analysed. RESULTS: There was no association between AD and any allele or genotype of AACT polymorphism; AACT polymorphism was not associated with AD ApoE epsilon4 or without ApoE epsilon4. In AACT*AT and AACT*TT genotypes, ApoE epsilon4 allele was associated with AD, but no association was observed in AACT*AA genotype. CONCLUSION: AACT may not be associated with AD in Chinese, and this effect can not be influenced by ApoE epsilon4, but AACT gene polymorphism may affect the association between ApoE epsilon4 allele and AD.

Tang G, Zhang M, Jiang S, Wu X, Jin T, Gu N, Lin S, Qian Y, Wang D, Wang H. · Shanghai Mental Health Center, Shanghai 200030 P.R.China. · Zhonghua Yi Xue Yi Chuan Xue Za Zhi. · Pubmed #9949230 No free full text.

Abstract: OBJECTIVE: To detect the relationship between Presinilin 1(PS1) intronic polymorphism and Alzheimer's disease(AD) in Chinese. METHODS: PS1 intronic polymorphism was genotyped in 58 early-onset AD cases(EOAD), 65 late-onset AD cases (LOAD) and 157 age-matched controls by using PCR methods and RFLP typing. Then the association between PS1 polymorphism and AD was analyzed. RESULTS: (1) In EOAD cases, the frequency of allele 1 increased and the frequencies of allele 2 and genotype 2/2 decreased markedly, but in LOAD cases, no differences were observed. (2) EOAD was significantly associated with allele 1 (RR=2.29), P< 0.05), allele 2 (RR=0.44) and genotype 2/2(RR=0.23, P<0.05) of PS1 polymorphism, while LOAD showed no association with PS1 polymorphism. (3)PS1 polymorphism was associated with AD predominantly in non-ApoE epsilon4, female, early-onset cases. CONCLUSION: PS1 polymorphism was only associated with EOAD in Chinese, and this may be influenced by age of onset and sex.