Deciphering the presenilin‐nicastrin interaction in the Alzheimer's disease related gamma‐secretase complex

Alzheimer's disease (AD), the most common type of dementia, currently affects a rapidly increasing 5.1 million Americans. This ultimately fatal neurodegenerative disorder typically presents with mild short‐term memory loss which progresses to an inability to carry out regular daily functions and recognize loved ones. While the exact cause of AD is unknown, it is known that the characteristic build‐up of amyloid plaques around neurons plays an important role in the memory loss in AD patients. Amyloid plaques are composed of Abeta‐42 peptides produced by cleavage of the amyloid precursor protein by gamma‐secretase. Gamma‐secretase is a high molecular weight complex composed of presenilin 1 or presenilin 2, nicastrin, PEN‐2, and APH‐1a or APH‐1b. Research will be presented that shows that the C‐terminus of presenilin 1 (amino acids 300–467) binds to nicastrin (amino acids 312–369). Progress on the binding of mutant presenilins and nicastrins that lead to increased or decreased production of Abeta‐42 will also be presented. An increased awareness of the binding specifications of the presenilin 1 C‐terminus to nicastrin, necessary for the formation of the gamma‐secretase high molecular weight complex, will give insight into the production of Abeta‐42, and thus a greater understanding of ways in which its production may be blocked.