Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks

Abstract

Alzheimer's disease is the most frequent neurodegenerative disorder and the most common cause of dementia in the elderly. Diverse lines of evidence suggest that amyloid-β (Aβ) peptides have a causal role in its pathogenesis, but the underlying mechanisms remain uncertain. Here we discuss recent evidence that Aβ may be part of a mechanism controlling synaptic activity, acting as a positive regulator presynaptically and a negative regulator postsynaptically. The pathological accumulation of oligomeric Aβ assemblies depresses excitatory transmission at the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level. Aβ-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. Strategies that block these Aβ effects may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are discussed.

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…High levels of Aβ have been shown to reduce glutamatergic synaptic transmission and cause synaptic loss, as shown by evidence from both in vivo and in vitro studies (Palop & Mucke, 2010). Aβ can control synaptic activity, depress excitatory transmission at the synaptic level, while triggering aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level (Palop & Mucke, 2010).…”

“…High levels of Aβ have been shown to reduce glutamatergic synaptic transmission and cause synaptic loss, as shown by evidence from both in vivo and in vitro studies (Palop & Mucke, 2010). Aβ can control synaptic activity, depress excitatory transmission at the synaptic level, while triggering aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level (Palop & Mucke, 2010). Using a tauopathy mouse model with in vivo intracellular and extracellular recordings, pathological tau was found to alter neocortical neuronal oscillatory patterns and firing patterns (Menkes‐Caspi et al, 2015).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Importantly, ApoE4 strongly interferes with these synapse-enhancing functions of Reelin by sequestering ApoE receptors in intracellular compartments (Chen et al 2010) (Fig. 3), thus providing a novel mechanism by which accelerated spine loss, increased tau phosphorylation (Kocherhans et al 2010), loss of network homeostasis Palop and Mucke 2010), and earlier disease onset through loss of neuroprotective compensatory bandwidth (Korwek et al 2009) can be readily explained. This mechanism is also consistent with the finding that ApoE4 reduces spine density and dendritic complexity in cortical neurons in vivo (Dumanis et al 2009).…”

Maladie d’Alzheimer, peptide β-amyloïde et synapses

“…Il est probable que l'altération de la fonction synaptique aille au-delà d'une altération de cette forme conventionnelle de plasticité synaptique. En particulier, les réseaux hippocampiques pourraient devenir hyperexcitables chez les souris transgéniques par des mécanismes de compensation qui affectent les synapses inhibitrices GABAergiques [2]. Ces souris pré-sentent une plus forte susceptibilité au déclenchement de crises épileptiques, ce qui est à mettre en rapport des peptides de taille variable, dont les principaux sont les peptides A40 et A42.…”

“…Cependant, il n'a pas été possible d'établir une corré-lation entre la sévérité des déficits cognitifs chez les patients atteints et le nombre de plaques amyloïdes détectées sur le cerveau post-mortem. Au moins dans les premières étapes du développement de la MA, ce serait plutôt l'accumulation progressive d'oligomères solubles de peptides -amyloïdes dans le cerveau qui serait neurotoxique [1,2]. Une meilleure connaissance des mécanismes moléculaires et cellulaires expliquant la neurotoxicité des oligomères de peptide A est indispensable pour le développement de thérapies efficaces à un stade précoce de la MA.…”