Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by memory loss and cognitive impairment. Whereas most AD cases are sporadic, some are caused by mutations in early-onset familial AD (FAD) genes. One FAD gene encodes presenilin 1 (PS1), and a PS1 mutation in methionine 146 impairs homeostatic synaptic plasticity (HSP). We have previously shown that Ca(2+) and calcineurin activity are critical regulators of HSP. Here, we confirm that endoplasmic reticulum-mediated Ca(2+) signals are increased in mutant PS1 neurons. We further show that calcineurin activity is abnormally elevated in the mutant and that inhibition of increased calcineurin activity stabilizes GluA1 phosphorylation, promoting synaptic trafficking of Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, contributing to the recovery of impaired HSP found in the mutant. Because HSP is suggested to have roles during learning and memory formation, increased calcineurin activity-induced impairment of HSP can cause cognitive decline in FAD. Thus, reducing abnormally increased calcineurin activity in AD brain may be beneficial for improving AD-related cognitive decline.
Keywords: AMPA receptor; Alzheimer’s disease; Calcineurin; Homeostatic synaptic plasticity; Presenilin 1.
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