Amyloid-β-induced action potential desynchronization and degradation of hippocampal gamma oscillations is prevented by interference with peptide conformation change and aggregation

Abstract

The amyloid-β hypothesis of Alzheimer's Disease (AD) focuses on accumulation of amyloid-β peptide (Aβ) 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. The aim of this study was to elucidate the cellular and synaptic mechanisms underlying the Aβ-induced degradation of gamma oscillations in AD, to identify aggregation state(s) of Aβ that mediate the peptides neurotoxicity, and to test ways to prevent the neurotoxic Aβ effect. We show that Aβ(1-42) in physiological concentrations acutely degrades mouse hippocampal gamma oscillations in a concentration- and time-dependent manner. The underlying cause is an Aβ-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 Aβ, as well as a designed ligand and a BRICHOS chaperone domain, we provide evidence that the severity of Aβ neurotoxicity increases with increasing concentration of fibrillar over monomeric Aβ forms, and that Aβ-induced degradation of gamma oscillations and excitatory/inhibitory equilibrium is prevented by compounds that interfere with Aβ aggregation. Our study provides correlative evidence for a link between Aβ-induced effects on synaptic currents and AD-relevant neuronal network oscillations, identifies the responsible aggregation state of Aβ and proofs that strategies preventing peptide aggregation are able to prevent the deleterious action of Aβ on the excitatory/inhibitory equilibrium and on the gamma rhythm.

Keywords: Alzheimer's disease; BRICHOS domain; amyloid-β peptide; gamma oscillations; hippocampus; neuronal synchronization.

Figure 1.

Effects of Aβ on hippocampal gamma oscillations. A, Example traces and example power spectra of control gamma oscillations and their degradation by increasing concentrations of Aβ. B, Summary box plot of gamma oscillation degradation by increasing concentrations of Aβ. C, Example traces and example power spectra of control gamma oscillations and their degradation by increasing exposure times to 50 nm Aβ. D, Summary box plot of gamma oscillation degradation by increasing exposure times to 1 μm Aβ and 50 nm Aβ (inset).

Figure 2.

Aβ desynchronizes PC firing. A, Degradation of gamma oscillation power over time by Aβ. B, Gamma oscillation frequency remains unchanged by Aβ. C, AP frequency of PCs is increased by Aβ. D, AP firing phase remains unchanged by Aβ. E, F, AP firing window increases after exposure to Aβ.

Figure 3.

Aβ alters balance between excitation and inhibition. A, In an activated network (100 nm KA), Aβ increases EPSC charge transfer and decreases IPSC charge transfer. These changes are based on an Aβ-induced increase of EPSC frequency and amplitude and a decrease of IPSC frequency and amplitude. B, In a quiescent network, Aβ increases EPSC charge transfer and decreases IPSC charge transfer. These changes are based on an Aβ-induced increase of EPSC frequency and amplitude and a decrease of IPSC frequency and amplitude.

Figure 4.

Severity of Aβ effect increases with fibrillization. A, Electron micrographs of Aβ_1-42 preparations negatively stained with uranyl acetate. Monomeric: in the SEC-purified Aβ monomer, no aggregated material was found. Mixed: the non-SEC purified Aβ contained aggregated material but also scarce fibrils. Fibrillar: after incubation of monomeric SEC-purified Aβ at 37°C, fibrils were abundant. B, Example traces and example power spectra of control gamma oscillations and their degradation by monomeric, mixed, and fibrillar Aβ. C, Summary box plot of gamma oscillation degradation by monomeric, mixed, and fibrillar Aβ.

Figure 5.

Prevention of gamma degradation by interference with Aβ folding and aggregation. A, Example traces and example power spectra of control gamma oscillations and prevention of their degradation by Aβ in the presence of a designed ligand. B, Summary box plot of prevention of gamma oscillation degradation by monomeric, mixed, and fibrillar Aβ in the presence of a designed ligand. C, Example traces and example power spectra of control gamma oscillations and prevention of their degradation by Aβ in the presence of a chaperone. D, Summary box plot of prevention of gamma oscillation degradation by monomeric, mixed, and fibrillar Aβ in the presence of a BRICHOS chaperone.

Figure 6.

Preservation of excitatory/inhibitory balance by interference with Aβ folding and aggregation. A, In an activated network (100 nm KA), a designed ligand prevents the Aβ-induced increase in EPSC charge transfer and decrease in IPSC charge transfer. B, In an activated network (100 nm KA), a BRICHOS chaperone prevents the Aβ-induced increase in EPSC charge transfer and decrease in IPSC charge transfer.