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Xuemin Xu PhD: Tokyo Institute of Technology, Japan A301a Veterinary Teaching Hospital |
Keywords:
Alzheimer's disease, Neurodegenerative disorder, Presenilin, PSAP, Apoptosis
Research Area:
The mechanism of neuronal cell death, specifically, apoptotic cell death found in Alzheimer's disease and other Neurodegenerative disorder. The normal and pathological function(s) of Alzheimer's disease associated proteins including apolipoprotein E, presenilin, and presenilin-associated protein
Description of Research:
The long-term objective of our research program is to determine the molecular and cellular mechanism of neuronal death of Alzheimer's disease. During the past decade, three genes have been identified as Alzheimer's disease causative genes. They are amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2). In addition, apolipoprotein E (apoE) is also believed as a risk factor of Alzheimer's disease. Several other gene products have also been speculated to be involved in Alzheimer's disease; however, the concept has not been well established. Although a great deal of progress has been made by the researchers in this field during the past years, there are still a lot of questions remain to be solved regarding the normal biological function and the mechanisms by which these genes cause Alzheimer's disease.
Among these identified Alzheimer's disease genes, mutations in the PS1 gene account for the majority of familial forms of Alzheimer's disease. Regarding the pathological function of PS1, several hypotheses have been proposed, one of the hypotheses is that the PS1 protein is involved altered proteolytic processing of the amyloid precursor protein (APP) result in the production of a greater proportion of longer, more fibrillogenic forms of -amyloid (A ). Several recent studies have shown that PS1 plays an important role in regulating the - secretase cleavage of APP and it has also been hypothesised that PS may function as the -secretase enzyme per se. The other hypothesis is that PS1 may be involved in an intracellular signaling pathway that regulates cell death or survive. This speculation is based on the finding that overexpression of the C-terminal fragment of PS1 protects cells from apoptosis, a programmed cell death and that mutant PS1 increases the vulnerability of cells to apoptotic stimuli. However, the molecular base underlying the mechanism thereby PS1 is involved in apoptosis remains elusive. Using the yeast two-hybrid system, we identified a novel molecule that interacts with the C-terminal of PS1. More interestingly, our recent experiments revealed that this new molecule causes apoptotic cell death when it is overexpressed. This finding provides a new insight into the biological function of this novel protein. This finding also established for the first time a molecular link between PS1 and an apoptotic cascade. This finding may open a new avenue to determine the normal and pathological function of PS1 and the mechanism by which PS1 is involved in neuronal death in Alzheimer's disease. Currently, our research is focused on the characterization of this newly identified molecule and determination of its functional relationship with PS1, specifically in apoptosis.
Selected Publications: