Ion modulation restores local synaptic function in APOE4 neuronal networks despite persistent impairments in global network organization

Abstract

The apolipoprotein E epsilon 4 (APOE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD), which accounts for the vast majority of AD cases. Ion dysfunction has emerged as a central mechanism involved in APOE4-related pathology, reflecting the importance of ion homeostasis for cell membrane excitability, synaptic transmission, and plasticity. We have previously demonstrated that ion dysfunction contributes to early AD-related network vulnerability, and that engaging synaptic plasticity mechanisms via ion modulation can restore network balance in neurodegenerative disease. Here, we investigated whether synaptic mobilization by ion modulation could ameliorate APOE4-associated dysfunction in human neuronal networks compared with isogenic APOE3 controls. APOE4 networks exhibited progressive structural and functional deterioration, manifesting as increased neurite length, reduced neurite branching, and reduced firing rate and number of active recording electrodes. This was accompanied by compensatory hypersynchronization, rendering networks vulnerable to pathological spread, and reduced synaptic AMPAR levels compared with isogenic APOE3 control networks. Modulating ion homeostasis restored the local firing dynamics and stabilized synaptic AMPAR levels. However, the elevated synchronization and aberrant morphology of APOE4 networks were not alleviated by engaging synaptic plasticity mechanisms, demonstrating that APOE4 networks retain a capacity for adaptive plasticity enabling restoration of local neuronal function, but that this recovery does not extend to higher-order network organization.