Amyloid-beta-Induced Action Potential Desynchronization and Degradation of Hippocampal Gamma Oscillations Is Prevented by Interference with Peptide Conformation Change and Aggregation

作者：Kurudenkandy Firoz Roshan; Zilberter Misha; Biverstal Henrik; Presto Jenny; Honcharenko Dmytro; Stromberg Roger; Johansson Jan; Winblad Bengt; Fisahn Andre^*

来源：Journal of Neuroscience, 2014, 34(34): 11416-11425.

DOI：10.1523/JNEUROSCI.1195-14.2014

• Alzheimer%26apos
• s disease
• amyloid-beta peptide
• BRICHOS domain
• gamma oscillations
• hippocampus
• neuronal synchronization

The amyloid-beta hypothesis of Alzheimer%26apos;s Disease (AD) focuses on accumulation of amyloid-beta peptide (A beta) as the main culprit for the myriad physiological changes seen during development and progression of AD including desynchronization of neuronal action potentials, consequent development of aberrant brain rhythms relevant for cognition, and final emergence of cognitive deficits. %26lt;br%26gt;The aim of this study was to elucidate the cellular and synaptic mechanisms underlying the A beta-induced degradation of gamma oscillations in AD, to identify aggregation state(s) of A beta that mediate the peptides neurotoxicity, and to test ways to prevent the neurotoxic A beta effect. %26lt;br%26gt;We show that A beta(1-42) in physiological concentrations acutely degrades mouse hippocampal gamma oscillations in a concentration- and time-dependent manner. The underlying cause is an A beta-induced desynchronization of action potential generation in pyramidal cells and a shift of the excitatory/inhibitory equilibrium in the hippocampal network. Using purified preparations containing different aggregation states of A beta, as well as a designed ligand and a BRICHOS chaperone domain, we provide evidence that the severity of A beta neurotoxicity increases with increasing concentration of fibrillar over monomeric A beta forms, and that A beta-induced degradation of gamma oscillations and excitatory/inhibitory equilibrium is prevented by compounds that interfere with A beta aggregation. %26lt;br%26gt;Our study provides correlative evidence for a link between A beta-induced effects on synaptic currents and AD-relevant neuronal network oscillations, identifies the responsible aggregation state of A beta and proofs that strategies preventing peptide aggregation are able to prevent the deleterious action of A beta on the excitatory/inhibitory equilibrium and on the gamma rhythm.

• 出版日期2014-8-20