Biomedical subjects

Roger M Nitsch

Publications and source records attributed to Roger M Nitsch.

58 records · Page 4Linked to original sources

PubMed2002

Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease.

Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.

5' Untranslated Regions↗

PubMed2002

CST3 genotype associated with exudative age related macular degeneration.

AIMS: To determine whether allelic variants of the cystatin C gene CST3 are genetically associated with exudative age related macular degeneration (ARMD). Cystatin C is a cysteine protease inhibitor that regulates the activity of cathepsin S, a protease with central regulatory functions in retinal pigment epithelial cells. METHODS: CST3 of 167 patients with exudative ARMD was genotyped by using polymerase chain reaction of genomic DNA and restriction enzyme digestion with KspI and compared with those of 517 control subjects. Patients and controls were white. RESULTS: There was a significant difference in genotype counts between patients and controls (chi(2) = 7.158, df = 2; Fisher's exact test: p = 0.037). There was no significant difference in allele frequencies between patients and controls and between controls from Germany, Switzerland, Italy, and United States. The significant difference in genotype counts between patients and controls could be explained completely by an excess of the homozygous CST3 genotype B/B in patients with exudative ARMD (6.6%) over controls (2.3%), suggesting an odds ratio for ARMD in association with CST3 B/B of 2.97 (95% CI: 1.28-6.86). The results also suggest a stronger association of B/B with ARMD in males than in females. However, in both males and females there was a similar and significant effect of CST3 B/B on disease free survival assessed by Kaplan-Meier analysis. The mean disease free survival time in pooled males and females with genotypes A/A or A/B was 85 years (SE 1; 95% CI: 83-86) and 76 years (SE 2; 95% CI: 72-79) respectively in B/B homozygotes (log rank p = 0.0006). CONCLUSION: Genotyping data, the absence of a significant difference in allele frequencies between patients and controls, and survival analyses suggest an increased susceptibility for ARMD in CST3 B/B homozygotes. Therefore, CST3 B may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients. Functional correlates of the allelic CST3 variants A and B remain to be investigated.

Age Factors↗

PubMedDate not supplied

ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease.

Increased formation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). High cellular cholesterol load promotes Abeta formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.

ATP Binding Cassette Transporter 1↗

PubMedDate not supplied

Immunotherapy of Alzheimer disease.

Optimism regarding the treatment and prevention of Alzheimer disease has begun to replace the attitude of therapeutic nihilism that clouded the field for so many decades. Neurotransmitter-based therapy with AChEls and NMDA receptor antagonists are now in current use; anti-inflammatory and anti-oxidative approaches as well as compounds to block Abeta aggregation are being tested in the clinic; beta- and gamma-secretase inhibitors designed to reduce generation of Abeta peptides are under development. One of the more provocative developments in this field was the idea of vaccination against beta-amyloid. Despite vivid antagonism that was rapidly voiced by many concerned experts, there are actually several excellent reasons why brain beta-amyloid plaques are attractive immunotherapeutic targets for the treatment and prevention of AD.

Alzheimer Disease↗