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Science. 2019 Aug 9;365(6453):559-565. doi: 10.1126/science.aay0198.

A vicious cycle of β amyloid-dependent neuronal hyperactivation.

Author information

1
Institute of Neuroscience, Technical University of Munich, 80802 Munich, Germany.
2
Munich Cluster for Systems Neurology, Technical University of Munich, 80802 Munich, Germany.
3
Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
4
C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Institute of Neuroscience, Technical University of Munich, 80802 Munich, Germany. arthur.konnerth@tum.de.

Abstract

β-amyloid (Aβ)-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 Aβ-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 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 before plaque formation.

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