Modeling Presenilin-Dependent Familial Alzheimer's Disease: Emphasis on Presenilin Substrate-Mediated Signaling and Synaptic Function

Mutations inPSENgenes, which encode presenilin proteins, cause familial early-onset Alzheimer's disease (AD). Transgenic mouse models based on coexpression of familial AD-associated presenilin and amyloid precursor protein variants successfully mimic characteristic pathological features of AD, including plaque formation, synaptic dysfunction, and loss of memory. Presenilins function as the catalytic subunit ofγ-secretase, the enzyme that catalyzes intramembraneous proteolysis of amyloid precursor protein to releaseβ-amyloid peptides. Familial AD-associated mutations in presenilins alter the site ofγ-secretase cleavage in a manner that increases the generation of longer and highly fibrillogenicβ-amyloid peptides. In addition to amyloid precursor protein,γ-secretase catalyzes intramembrane proteolysis of many other substrates known to be important for synaptic function. This paper focuses on how various animal models have enabled us to elucidate the physiological importance of diverseγ-secretase substrates, including amyloid precursor protein and discusses their roles in the context of cellular signaling and synaptic function.