Dysfunctional γ-Secretase in Familial Alzheimer's Disease

Abstract

Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease. Dominant missense mutation in the presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer's disease (FAD). As presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that presenilins are dysfunctional in FAD. γ-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function-the carboxypeptidase trimming of initially formed long Aβ peptides containing most of the transmembrane domain to shorter secreted forms-is an emerging common feature of FAD-mutant γ-secretase complexes.

Keywords: Amyloid; Biochemistry; Genetics; Protease.

Figure 1.. Production of Aβ from APP.

APP is an integral membrane protein, with the Aβ portion derived in part from the single transmembrane domain. β-Secretase is a membrane-tethered aspartyl protease in the pepsin family that cleaves APP outside the membrane to release the large extracellular domain of APP (APP_s-β). The membrane-bound remnant APP CTF-β) is then cleaved by γ-secretase to produce Aβ and the APP intracellular domain (AICD). γ-Secretase a membrane-embedded aspartyl protease composed of four different membrane proteins. Presenilin NTF/CTF heterodimer (blue) is the catalytic component of the γ-secretase complex that carries out proteolysis within the APP transmembrane domain.

Figure 2.. Processive proteolysis of the APP transmembrane domain by γ-secretase.

An endoproteolytic activity of the enzyme cleaves at the ε site within the transmembrane domain close to the membrane-cytosol interface to give long Aβ peptides Aβ48 and Aβ49 and the APP intracellular domain (AICD). The carboxypeptidase activity of γ-secretase then trims Aβ48 and Aβ49 in 3–4 amino acid increments.

Figure 3.. Dual-pathway proteolysis of APP by γ-secretase.

Cleavage at the ε site occurs at one of 2 sites, resulting in Aβ49 and AICD50–99 or Aβ48 and AICD49–99. Subsequent carboxypeptidase trimming leads to two Aβ product lines: Aβ49→Aβ46→Aβ43→Aβ40 and Aβ48→Aβ45→Aβ42→Aβ38.