Functional Role of Each Component in Gamma Secretase Complex

Amyloid hypothesis is widely accepted as the centerpiece of Alzheimer’s disease (AD) pathogenesis. It is believed that the accumulation of amyloid beta (Ab) is the major deterministic factor of AD and the most important causative factor is the ratio of Ab42/Ab40. Gamma(g)-secretase defines the length of Ab and is composed of at least four subunits: presenilins (PS1 or PS2), nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer 2 (Pen-2). They have been reported to have different roles in g-secretase. For example, PS were believed as the catalytic components in g-secretase; NCT was recognized as a substrate receptor; Pen-2 was regarded as necessary for the endoproteolysis of PS which necessary for the activity of PS; and Aph-1 was known as important for stabilization of the other g-secretase components. However, these notions having been challenged by new and controversial findings, which make the functions of these components remain elusive. Therefore, the goal of my research projects is to address these controversial issues by systematically investigate the function of these components in g-secretase activity and in apoptosis.

Our results demonstrate that 1) Aph-1 is dispensable for g-secretase catalyzed processing of both Notch and amyloid beta precursor protein (APP); 2) NCT is crucial for APP processing, but is not absolutely required for Notch processing; 3) Pen-2 is necessary for the processing of both Notch and APP processing; 4) Pen-2 is the most important component for recruiting substrates; 5) Knockout of Aph-1 sensitizes cells to apoptosis; 6), PS1 accounts for the majority of the g-secretase activity the PS1C₂₉₉ (from amino acid 299 to the end amino acid 467) is the most active form of PS1 C. These new findings not only significantly contribute to our knowledge of the biochemistry of g-secretase and its catalyzed Notch and APP processing, but also provide valuable information for the development of therapeutic strategy of prevention and treatment of AD.