| Research Abstract |
Deposition of amyloid β peptides (Aβ) as senile plaques (SP) is an invariant feature of Alzheimer's disease (AD) brains. Aβ is a 40-42 amino acid peptide that is proteolytically produced from βAPP through sequential cleavages by β- and γ-secretases. The role of presenilin (PS) as a catalytic subunit of γ-secretase is recently highlighted. We and others have shown that mutations in PS (i.e., PS1 and PS2) genes linked to familial AD (FAD) increase production and secretion of Aβ42, that initially and predominantly deposits in the brains of patients with all types of AD.In the present study, we showed that modifications at the C terminus of PS abolish stabilization of PS fragments as well as overproduction of Aβ42 on FAD mutant basis, suggesting that stable fragment forms of PS is the pathologically active species. We further searched for PS subdomains that is critical to its stabilization and function, and identified another motif which we designated "PALP". PALP motif is located at the proximal site of the C terminus of PS (corresponding to residues 414-417 based on human PS2) and is highly conserved, and mutations in drosophila PS and spe-4 in C.elegans that replace the 1st Pro of PALP with Leu lead to Notch phenotype caused by loss-of-function of PS, although the mechanism whereby these mutations deteriorate PS function remained unknown. We found that human PS harboring Pro to Leu mutation at the 1st residue of PALP fails to promote Aβ42 overproduction on FAD mutant basis as well as Notch processing through failure in stabilization and high-molecular-weight complex formation of PS, as observed with modifications at PS C terminus. Hence, search for cofactors that serve as stabilizing or regulatory subunit (s) of PS/γ-secretase, as well as understanding of the mechanism of γ-cleavage, should be the next goal in PS research.
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