A Potential Drug Target for Alzheimer's Disease

Joshi and co-workers show in this research article data suggesting that Golgi is a potential drug target for AD. In this study, APPswe/PS1?E9, a widely used AD transgenic mouse model was utilized, expressing an APP Swedish mutation and the exon 9 deletion mutant of human PS1. Initially, it was demonstrated that Golgi fragmentation occurred in this transgenic mouse model, as well as in tissue culture cells that were doubly transfected with cDNAs encoding both mutants. Application of specific protease inhibitors to AD cells led to a pronounced reduction in Golgi fragmentation, strongly illustrating A? accumulation as a cause for Golgi fragmentation. What could be the mechanisms for A?-mediated Golgi fragmentation?

As kinase (cyclin-dependent kinase-5, cdk5) activation has been previously reported as a result of A? production, Golgi fragmentation was subsequently reduced in the current study upon the addition of kinase inhibitors to AD cells. The highly organized stacked Golgi structure is supported by several Golgi structural proteins, such as GRASP65, an important component tethering the cisternae into stacks and a major mitotic kinase target.

The authors further found that GRASP65 was highly phosphorylated in AD cells through immunoprecipitation and Western blot studies, and GRASP65 phosphorylation was due to cdk5 that was activated by A? accumulation. After identification and confirmation of Golgi fragmentation mechanism, nonphosphorylatable mutants of GRASP proteins were transfected in AD cells, and Golgi structure and function were rescued. This proof-of-principle study points to molecular causes for Golgi fragmentation and also a potential new target for AD treatment.

AML is a rapidly progressing hematologic cancer characterized by uncontrolled proliferation of immature blast cells in the bone marrow. The American Cancer Society estimates there will be approximately 18,860 new cases of AML and approximately 10,460 deaths in the U.S. in 2014. AML patients with relapsed or refractory disease and newly diagnosed AML patients over 60 years of age with poor prognostic risk factors typically die within one year, resulting in an acute need for new treatment options for these patients.

MDS is a hematopoietic stem cell neoplasm characterized by disordered and ineffective hematopoiesis which results in irreversible decline in the number and quality of blood-forming cells. Patients often develop severe anemia requiring frequent blood transfusions. In most cases progressive bone marrow failure results in neutropenia and thrombocytopenia, and in about one third of patients the disease progresses into AML, usually within a few years.

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