Involvement of presenilin 1 in the generation of the amyloid beta-peptide : lessons from a cellular model lacking the amyloidogenic pathway
(2004)
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- Authors
- Supervisors
- Octave, Jean-Noël
- Abstract
- Alzheimer's disease (AD) is the most common form of dementia, affecting 15 million people worldwide, a figure quickly increasing with the ageing of Western populations. As the cause of the disease is still unclear, our possibilities of therapeutic intervention are unfortunately limited to symptomatic handling. Nevertheless, evidence accumulated over the last few years that the accumulation of amyloid beta-peptide (Ab) oligomers and fibrils could be a cornerstone in the development of neurodegeneration. The mechanisms leading to the liberation of the Ab peptide from its precursor by the beta- and gamma-secretase activities have been investigated in this thesis using a cellular model devoid of such activities. More particularly, the function of presenilin 1 (PS1), mutations of which are the main cause of early-onset familial AD, in the ultimate cleavage leading to Ab production was scrutinized. This polytopic protein, the first one to be shown mandatory for gamma-secretase activity, has recently been shown to be dispensable for the production of some Ab species inside as well as outside cells. As gamma-secretase inhibition is a promising way to lower Ab production and treat patients, it was thus important to assess if PS1 is indeed a new kind of protease responsible for a crucial step in Ab generation. In this thesis, we explored the function of PS1 in insect and Chinese hamster cells, as well as in rat and mouse neurons. We show that PS1 binds to the substrates of gamma-secretase, stabilizing them and increasing their cellular steady-states. This results in their increased availability for gamma-secretase cleavage and therefore in an increased production of Ab. Hence, we concluded that the influence of PS1 on the generation of Ab occurs upstream of the gamma-secretase activity and suggest that another protease is responsible for the ultimate cleavage of the amyloid precursor protein. Moreover, the fact that PS1 binds to the gamma-secretase substrates without cleaving them suggests it could have a chaperone role. As the maturation and trafficking of PS1 in the secretory pathway is known to be tightly regulated, PS1 could be involved in the transportation of gamma-secretase substrates towards compartments where gamma-secretase activity takes place, without excluding it could participate in the recruitment/regulation of gamma-secretase activity or in the presentation of the substrate to the enzyme. These advances in understanding the role of PS1 in Ab generation might well reconciliate numerous discordant data published in this field.
- Affiliations
Citations
Pitsi, D. (2004). Involvement of presenilin 1 in the generation of the amyloid beta-peptide : lessons from a cellular model lacking the amyloidogenic pathway. https://hdl.handle.net/2078.5/110727