The γ-secretase complex: from structure to function

Front Cell Neurosci. 2014 Dec 11;8:427. doi: 10.3389/fncel.2014.00427. eCollection 2014.


One of the most critical pathological features of Alzheimer's disease (AD) is the accumulation of β-amyloid (Aβ) peptides that form extracellular senile plaques in the brain. Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavage by β- and γ-secretases. γ-secretase is a high molecular weight complex minimally composed of four components: presenilins (PS), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2). In addition to APP, γ-secretase also cleaves many other type I transmembrane (TM) protein substrates. As a crucial enzyme for Aβ production, γ-secretase is an appealing therapeutic target for AD. Here, we summarize current knowledge on the structure and function of γ-secretase, as well as recent progress in developing γ-secretase targeting drugs for AD treatment.

Keywords: Alzheimer’s disease; anterior pharynx defective 1; nicastrin; presenilin; presenilin enhancer 2; γ-secretase.

Publication types

  • Review