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

Amyloid- Impairs Synaptic Inhibition via GABAA Receptor Endocytosis

“…A similar mechanism has previously been shown to underlie the A␤-induced decrease of glutamatergic synaptic transmission (Hsieh et al, 2006). Of note, no p4-related upregulation of IPSCs was seen in the present study, as originally reported by Kittler et al (2000). However, the absence of a p4-induced increase of GABA receptors is in line with previous data from cortical pyramidal neurons (Kurotani et al, 2008), indicating that this phenomenon may be cell-type specific.…”

“…The prevention of the A␤-induced decline of IPSCs by p4, a peptide that inhibits the dynaminmediated removal of GABA A receptors from the plasma membrane (Kittler et al, 2000), indicates that A␤ exerts its effect via receptor endocytosis. A similar mechanism has previously been shown to underlie the A␤-induced decrease of glutamatergic synaptic transmission (Hsieh et al, 2006).…”

“…In particular, GABA A receptors are known to be removed from the plasma membrane by clathrin-mediated endocytosis, a process that requires interactions between dynamin and amphiphysin (Kittler et al, 2000). To investigate whether A␤ affects GABA A receptor endocytosis, IPSCs were elicited with the dynamin inhibitory peptide p4 (50 M) intracellularly applied via the patch pipette in combination with the protease inhibitors leupeptin (0.1 mM) and bestatin (0.1 mM) (Fig.…”

“…To investigate whether A␤ affects GABA A receptor endocytosis, IPSCs were elicited with the dynamin inhibitory peptide p4 (50 M) intracellularly applied via the patch pipette in combination with the protease inhibitors leupeptin (0.1 mM) and bestatin (0.1 mM) (Fig. 4) (Kittler et al, 2000). When p4 was allowed to diffuse into cells, IPSCs were no longer significantly reduced by A␤ to 85 Ϯ 9% of control (n ϭ 9, p Ͼ 0.1, paired t test) (Fig.…”

Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

“…For the amyloid ␤-peptide (A␤) 4 associated with Alzheimer disease, many studies indicate that pre-fibrillar intermediates present during the aggregation trigger neuronal dysfunction, rather than the fibrils per se (14). However, mature fibrils can also exert more potent toxic effects than pre-fibrillar forms of A␤ in certain experimental systems (15).…”