A vicious cycle of β amyloid-dependent neuronal hyperactivation.

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.

• Authors: Benedikt Zott, Manuel M Simon, Wei Hong, Felix Unger, Hsing-Jung Chen-Engerer, Matthew P Frosch, Bert Sakmann, Dominic M Walsh, Arthur Konnerth
• Journal: Science (New York, N.Y.) (Science) Vol. 365 Issue 6453 Pg. 559-565 (08 09 2019) ISSN: 1095-9203 [Electronic] United States
• PMID: 31395777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Amyloid beta-Peptides
• Glutamic Acid

Topics

• Alzheimer Disease (physiopathology)
• Amyloid beta-Peptides (chemistry, metabolism)
• Animals
• CA1 Region, Hippocampal (physiopathology)
• Disease Models, Animal
• Glutamic Acid (metabolism)
• Humans
• Long-Term Potentiation
• Mice
• Neurons (physiology)
• Plaque, Amyloid (metabolism)
• Protein Multimerization