Clinical issue

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Some cases of the disease (FAD) are inherited through causative defects in the genes for amyloid precursor protein (APP), presenilin 1 (PS1) or presenilin 2 (PS2). APP is a type 1 (single-pass) transmembrane protein that is cleaved by γ-secretase; presenilin contains two essential aspartyl residues that constitute the active site of the protease. γ-Secretase functions as a multiprotein complex with the accessory proteins Nicastrin, Pen2 and Aph1. Pathogenesis of FAD results from the misregulation of γ-secretase cleavage of APP, rather than by the absence of cleavage.

γ-secretase cleaves other type 1 transmembrane proteins and plays a role in diverse clinically relevant pathways, including cell adhesion and cell differentiation. γ-Secretase cleavage of Notch is essential for normal embryogenesis, and loss of any of the γ-secretase components in mammals has an embryonic lethal, Notch-like phenotype.

Results

The authors show that the ancient organism Dictyostelium has highly diverged γ-secretase subunits that can precisely process ectoptic human APP. Thus, this key regulatory pathway is evolutionarily conserved through hundreds of millions of years. In Dictyostelium, γ-secretase activity is necessary for phagocytosis, a process also required for innate immune response in mammalian cells. Similar to the complex metazoa, γ-secretase components in Dictyostelium are required for cell-fate determination. Dictyostelium is a unique system that is experimentally amenable to study γ-secretase function.

Implications and future directions

Understanding the function and regulation of presenilin-dependent γ-secretase cleavage events is essential for identifying new therapeutic approaches for treating AD. By expressing FAD mutations in Dictyostelium, we might be able to recapitulate aberrant cleavage of APP. Such cell lines might present a relatively simple and inexpensive system for the high-throughput screening of small-molecule libraries to identify novel pharmaceutical agents. Expression of mutant presenilin can also be used to study causative effects of γ-secretase misregulation on phagocytosis and developmental pathways.

This model also has potential for understanding complex pathways involved in immunity. γ-Secretase in Dictyostelium functions in a primary role to regulate nutrient-particle capture via phagocytosis during cellular growth. In mammals, macrophages engulf invading pathogens and apoptotic cells by a mechanistically identical pathway. γ-secretase signaling is central both to phagocytosis in Dictystelium and to the immune response in mammalian cells. Studies in Dictyostelium that identify essential transmembrane protein targets that are cleaved by γ-secretase might uncover novel and conserved mechanistic pathways that regulate phagocytosis. The conservation of γ-secretase in Dictyostelium suggests it as a tractable model to understand AD and macrophage phagocytosis.