ASS234, As a New Multi-Target Directed Propargylamine for Alzheimer's Disease Therapy

During apoptosis, the mitochondrial network fragments. Using short hairpin RNAs for RNA interference, we manipulated the expression levels of the proteins hFis1, Drp1, and Opa1 that are involved in mitochondrial fission and fusion in mammalian cells, and we characterized their functions in mitochondrial morphology and apoptosis. Down-regulation of hFis1 powerfully inhibits cell death to an extent significantly greater than down-regulation of Drp1 and at a stage of apoptosis distinct from that induced by Drp1 inhibition. Cells depleted of Opa1 are extremely sensitive to exogenous apoptosis induction, and some die spontaneously by a process that requires hFis1 expression. Wild-type Opa1 may function normally as an antiapoptotic protein, keeping spontaneous apoptosis in check. However, if hFis1 is down-regulated, cells do not require Opa1 to prevent apoptosis, suggesting that Opa1 may be normally counteracting the proapoptotic action of hFis1. We also demonstrate in this study that mitochondrial fragmentation per se does not result in apoptosis. However, we provide further evidence that multiple components of the mitochondrial morphogenesis machinery can positively and negatively regulate apoptosis.

Microtubule associated protein tau is a phosphoprotein which potentially has 80 serine/threonine and 5 tyrosine phosphorylation sites. Normal brain tau contains 2-3 moles of phosphate per mole of the protein. In Alzheimer's disease brain, tau is abnormally hyperphosphorylated to a stoichiometry of at least three-fold greater than normal tau, and in this altered state it is aggregated into paired helical filaments forming neurofibrillary tangles, a histopathological hallmark of the disease. The abnormal hyperphosphorylation of tau is also a hallmark of several other related neurodegenerative disorders, called tauopathies. The density of neurofibrillary tangles in the neocortex correlates with dementia and, hence, is a rational therapeutic target and an area of increasing research interest. Development of rational tau-based therapeutic drugs requires understanding of the role of various phosphorylation sites, protein kinases and phosphatases, and post-translational modifications that regulate the phosphorylation of this protein at various sites, as well as the molecular mechanism by which the abnormally hyperphosphorylated tau leads to neurodegeneration and dementia. In this article we briefly review the progress made in these areas of research.