A vicious cycle of β amyloid−dependent neuronal hyperactivation

b-amyloid (Ab)–dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer’s disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Ab-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Ab-mediated hyperactivation. Ab-containing AD brain extracts and purified Ab dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Ab-dependent neuronal dysfunction that can be active before plaque formation.