A vicious cycle of amyloid β-dependent neuronal hyperactivation

• Published in: Science (American Association for the Advancement of Science) 2019-08, Vol.365 (6453), p.559-565
• Main Authors: Zott, Benedikt, Simon, Manuel M., Hong, Wei, Unger, Felix, Chen-Engerer, Hsing-Jung, Frosch, Matthew P., Sakmann, Bert, Walsh, Dominic M., Konnerth, Arthur
• Format: Article
• Language: English
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aay0198

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