Analysis of presenilin/γ-secretase complex responsible for the generation of Aβ in Alzheimer's disease

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Deposition of amyloid β peptides (Aβ) as senile plaques (SP) and cerebrovascular amyloid characterizes the neuropathology of Alzheimer's disease (AD). It has been shown that mutations in presenilin (i.e., PSi and PS2) genes linked to familial AD (FAD) increase production and secretion of Aβ42, an initially and predominantly depositing Aβ species in all types of AD. PS are involved in the γ-secretase cleavage of a subset of single-pass membrane proteins including β-amyloid precursor protein and Notch. γ-secretase activity requires the formation of a highly stable, high molecular weight (HMW) protein complex comprised of PS and other co-factor membrane proteins. We showed by RNA interference that Drosophila APH-1 (dAPH-1), an isologue of a Notch pathway component in Caenorabditis elegans, is required for γ-secretase activity to generate Aβ in Drosophila S2 cells. Overexpression of dAPH-1, together with nicastrin (NCT), dramatically increases the stabilization of Drosophila PS (Psn) holoproteins that are incorporated into a HMW protein complex. Inactivation of dPEN-2, another Psn cofactor, abrogates accumulation of Psn fragments, whereas promotes stabilization of Psn holoprotein. Co-expression of dPEN-2 with dAPH-1 and dNCT increases the formation of Psn fragments as well as γ-secretase activity to generate Aβ. These data suggest that: (i)APH-1 stabilizes PS holoprotein in collaboration with NCT, whereas PEN-2 elicits the final maturation of γ-secretase complex, conferring its activity and inducing endoproteolysis of PS and (ii)PS, NCT, APH-1 and PEN-2 represent the set of proteins that comprise the major framework of γ-secretase.