The role of 7-secretase in hippocampal synaptic transmission and activity-dependent synaptic plasticity

摘要

The gamma-secretase complex is responsible for the proteolytic processing of certain type I integral membrane proteins and is composed of four integral subunits: presenilin, nicastrin, Aph-1, and Pen-2 [39]. 7-Secretase not only mediates the activation of Notch receptors but also discrete steps in the processing of amyloids, including amyloid beta (Abeta1-42) via sequential proteolytic cleavages of amyloid precursor protein (APP). Different aggregation levels of Abeta have been associated with distinct neu-rophysiological or neuropathophysiological effects. For example, amyloid beta oligomers have been shown to alter long-term poten-tiation (LTP), efficiency of synaptic transmission and cognitive abilities [31,37,32,5]. The appearance of excess amyloids is one of the neuropathological hallmarks of Alzheimer's disease (AD) and is proposed to underlie the severe memory decline in AD patients [11,33,12]. Therefore, secretase inhibitors, which inhibit or modulate accumulation of amyloids were suggested as potential therapeutic targets against AD [6,7].