Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease.

Audrey Hector,Jonathan Brouillette

doi:10.3389/fnmol.2020.600084

Abstract

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

Highlights

Synapse loss that precedes neuronal death is the strongest predictor of cognitive decline in Alzheimer’s disease (AD) (Alzheimer’s, 2020)
A similar level of hyperactivity was observed in the CA1 region of the hippocampus in young (1–2 months of age) APP23×PS45 mice when Aβo begin to accumulate but no plaques are detected (Busche et al, 2012). These results suggest that hyperactivity is an early pathological event that depends on the accumulation of Aβo rather than plaques per se, and that plaques might serve as a reservoir of toxic Aβo that amplify this excessive neuronal activity responsible, at least in part, for the marked synaptic and neuronal losses observed around plaques (Hefendehl et al, 2016)
A myriad of studies performed in humans, cell cultures, human induced pluripotent stem cell (hiPSC) lines carrying familial AD mutations, AD mouse models, and wild-type mice injected with soluble Aβo indicate that neuronal hyperactivity is an early detrimental event in AD pathogenesis

Summary

Introduction

Synapse loss that precedes neuronal death is the strongest predictor of cognitive decline in Alzheimer’s disease (AD) (Alzheimer’s, 2020). Based on AD animal models, in vitro experiments and human studies, Aβo-induced neuronal hyperactivity has emerged as an early functional hallmark of AD which triggers synaptic failure, memory dysfunction, epileptiform activity, and neurodegeneration.

Results

Conclusion