Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis

Presenilin 1 (PS1) is a catalytic component of the gamma-secretase complex, responsible for the intramembraneous cleavage of more than 90 type I transmembrane proteins, including Alzheimer's disease (AD)-related amyloid precursor protein (APP). The gamma-secretase-mediated cleavage of the APP C-terminal membrane stub leads to the production of various amyloid beta (A beta) species. The assembly of A beta into neurotoxic oligomers, which causes synaptic dysfunction and neurodegeneration, is influenced by the relative ratio of the longer (A beta 42/43) to shorter A beta (A beta 40) peptides. The ratio of A beta 42 to A beta 40 depends on the conformation and activity of the PS1/gamma-secretase enzymatic complex. The latter exists in a dynamic equilibrium of the so called closed and open conformational states, as determined by the Forster resonance energy transfer (FRET)-based PS1 conformation assay. Here we review several factors that can allosterically influence conformational status of the enzyme, and hence the production of A beta peptides. These include genetic variations in PS1, APP and other gamma-secretase components, environmental stressors implicated in AD pathogenesis and pharmacological agents. Since closed PS1 conformation is the common outcome of many AD-related insults, the novel assays monitoring PS1 conformation in live/intact cells in vivo and in vitro might be utilized for diagnostic purposes and for validation of the potential therapeutic approaches.