Biological function of Presenilin and its role in AD pathogenesis

Abstract

Presenilins (PSs) are the catalytic core of γ-secretase complex. However, the mechanism of FAD-associated PS mutations in AD pathogenesis still remains elusive. Here we review the general biology and mechanism of γ-secretase and focus on the catalytic components - presenilins and their biological functions and contributions to the AD pathogenesis. The functions of presenilins are divided into γ-secretase dependent and γ-secretase independent ones. The γ-secretase dependent functions of presenilins are exemplified by the sequential cleavages in the processing of APP and Notch; the γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway, regulating calcium homeostasis and their interaction with synaptic transmission.

Figure 1

APP processing pathways. Under the physiological conditions, the majority of APP undergoes the non-amyloidogenic pathway. The α-secretase processes APP within the Aβ domain to generate C83 and this cleavage abolishes Aβ generation. In the amyloidogenic pathway, β-secretase processes APP at Asp¹ site to generate C99 fragment, which is the substrate for γ-secretase for Aβ generation.

Figure 2

Presenilin 1 structure. This diagram shows the amino acid sequence of PS1 and the distribution of the FAD-associated mutations. Blue circles represent the FAD-associated mutations and red circles indicate the two catalytic active aspartates.

Figure 3

γ-secretase complex and the formation of the catalytic pore of PS1. PS1 transmembrane domains (TMDs) are shown as columns with numbers. Without the assistance of other subunits, PS1 forms a relatively open pore structure within the membrane. Upon the binding of subunits, the PALP motif moves to the proximity of the catalytic center, and the catalytic structure is activated by the structural changes in TMDs of PS1.

Figure 4

Presenilin functions. This diagram divides the functions of presenilins into γ-secretase-dependent and γ-secretase-independent ones by the vertical dash line. The γ-secretase activity of presenilins are exemplified by APP processing and Notch processing. Other γ-secretase independent functions of presenilins include stabilizing β-catenin in Wnt signaling pathway, regulating calcium homeostasis and its interaction with synaptic transmission. APP, amyloid β precursor protein; AICD, APP intracellular domain; NICD, Notch intracellular domain; Nct, Nicastrin; IP3, Inositol trisphosphate receptor; SERCA, Sarco/endoplasmic reticulum Ca²⁺⁻ATPase; Ryan R, Ryanodine receptor; GSK, Glycogen synthase kinase.