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

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.

Interdependence of neural network dysfunction and microglial alterations in Alzheimer’s disease-related models

“…However, the causes and consequences of AD-associated network dysfunctions remain to be fully elucidated. Evidence obtained in AD-related mouse models suggests that the human amyloid precursor protein (hAPP) or some of its metabolites and the microtubule-associated protein tau (MAPT) causally contribute to these dysfunctions ( Palop and Mucke, 2016 ; Harris et al., 2020 ; Johnson et al., 2020 ; Chang et al., 2021 ; Hector and Brouillette, 2021 ). Indications that hypersynchronous network activity may promote disease progression include the observations that cognitive decline is faster in AD patients with detectable epileptiform activity than those without ( Vossel et al., 2016 ), that treatment with the antiepileptic drug levetiracetam (LEV) reverses functional magnetic resonance imaging abnormalities and reduces some cognitive deficits in people with amnestic mild cognitive impairment ( Bakker et al., 2012 , 2015 ), and that treatment with LEV, or its analog brivaracetam, suppresses epileptiform activity and reverses both synaptic deficits and cognitive impairments in different lines of hAPP transgenic mice ( Sanchez et al., 2012 ; Shi et al., 2013 ; Nygaard et al., 2015 ; Fu et al., 2019 ).…”

A quantitative model of sporadic axonal degeneration in theDrosophilavisual system

“…Further, imbalanced activity represents a potential trigger of neurodegeneration (Busche and Konnerth, 2016;Palop and Mucke, 2016;Palop et al, 2007;Sosulina et al, 2021). Neuronal hyperactivity has been detected in patients with mild cognitive impairment (MCI), a prodromal stage of AD, and in carriers of the APOE4 allele, the most important genetic risk factor for late-onset sporadic AD, as well as in many transgenic AD mice (Hector and Brouillette, 2020). Furthermore, activity imbalance at the circuit level is reported in Alzheimer's disease and in AD model systems and is considered a potential trigger of neurodegeneration (Busche and Konnerth, 2016;Palop and Mucke, 2016;Palop et al, 2007;Sosulina et al, 2021).…”

“…Recent evidence indicates that synaptic failure in AD is at least partly induced by neuronal hyperactivity in the early stages of the disease, and this mechanism could also be involved in developing a late-onset autosomal dominant inherited form of PD (Hector and Brouillette, 2020;Lucumi Moreno et al, 2021;Nuriel et al, 2017). We thus tested whether activity of PRCs is linked to the axonal degeneration described in our model.…”

Microglial P2X4 receptors promote ApoE degradation and cognitive deficits in Alzheimer disease

“…One interpretation for this discrepancy is that the reduced level of sAß observed in APP/PS1xKO may be sufficient to restore synaptic efficiency independently of synaptic structural changes, e.g. by directly regulating neuronal excitability alterations associated with Aß peptide deposit 39 .…”