The clinical and genetic relationships between Alzheimer's disease (AD) and glaucoma remain obscure. The aim of this study was to determine the prevalence of open-angle glaucoma (OAG) in patients with AD and whether the apolipoprotein E (APOE) 4 allele is associated with AD, with or without OAG, in Japanese. The groups consisted of 172 patients with the diagnostic criteria of AD and 176 age-matched controls. Ophthalmic examinations were conducted, and genomic analysis was performed by PCR and digestion of products with an enzyme. OAG was found in 41 (23.8%) of the AD patients, which was a significantly (p = 0.0002) higher prevalence than that in the controls (9.9%). Furthermore, there was no significant difference between intraocular pressures (IOPs) in AD patients with OAG and without OAG. The percentage of AD patients who carried an APOE epsilon4 allele (29.5%) was significantly (p = 0.0007) higher than that of the controls (9.1%). However, the percentage of AD patients with OAG who carried an APOE epsilon4 allele (35.7%) was not significantly different than that of AD patients without OAG (27.7%, p = 0.42). In summary, the prevalence of OAG is high in Japanese patients with AD, suggesting that common factors other than APOE may contribute to the two diseases.

No abstract

We have previously shown that nerve growth factor (NGF) withdrawal-induced death requires the activity of the small GTP-binding protein Cdc42 and that overexpression of an active form of Cdc42 is sufficient to mediate neuronal apoptosis via activation of the c-Jun pathway. Recently, a new mitogen-activated protein (MAP) kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1) which activates both the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways and plays pivotal roles in tumor necrosis factor-and Fas-induced apoptosis, has been identified. Therefore, we investigated the role of ASK1 in neuronal apoptosis by using rat pheochromocytoma (PC12) neuronal cells and primary rat sympathetic neurons (SCGs). Overexpression of ASK1-⌬N, a constitutively active mutant of ASK1, activated JNK and induced apoptosis in differentiated PC12 cells and SCG neurons. Moreover, in differentiated PC12 cells, NGF withdrawal induced a four-to fivefold increase in the activity of endogenous ASK1. Finally, expression of a kinase-inactive ASK1 significantly blocked both NGF withdrawal-and Cdc42-induced death and activation of c-jun. Taken together, these results demonstrate that ASK1 is a crucial element of NGF withdrawal-induced activation of the Cdc42-c-Jun pathway and neuronal apoptosis.

No abstract

Transforming growth factor-b (TGFb) conveys regulatory signals through multiple intracellular pathways, subsequently affecting various cellular functions. To identify new targets for TGFb, we studied the changes in the proteome of Mv1Lu lung epithelial cells in response to TGFb1 treatment. Thirty-eight non-abundant protein spots, affected by TGFb1, were selected, and proteins were identi®ed by peptide mass®ngerprinting (PMF). Among them, proteins involved in regulation of immune response, apoptosis, regulation of TGFb signalling, metabolism and DNA repair were identi®ed. Twenty-eight of the 38 proteins are new targets for TGFb1, thus suggesting novel ways of integration of TGFb signalling in intracellular regulatory processes. We show that TGFb1-dependent decrease in expression of one of the new targets, Rad51, correlates with a decrease in DNA repair ef®-ciency. This was evaluated by formation of nuclear Rad51-containing DNA repair complexes in response to DNA damage, by single cell gel electrophoresis and by cell survival assay. The TGFb1-dependent inhibition of DNA repair was reversed by ectopic overexpression of Rad51. Therefore, TGFb can promote DNA instability through down-regulation of Rad51 and inhibition of DNA repair.

Autologous scaffold-free TEC derived from synovial MSCs may be used for regenerative cartilage repair via a sutureless and simple implantation procedure. Registration: 000008266 (UMIN Clinical Trials Registry number).

These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma.

Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG.