Low concentrations of amyloid-beta oligomers induce synaptogenesis characteristic for mild cognitive impairment and alter the de novo proteome.

Alzheimer's disease (AD) is characterized by synaptic dysfunction and proteostatic imbalance, partly driven by amyloid-beta oligomers (Aβo). This study focuses on the effects of low-concentration Aβo exposure on synaptic architecture and de novo protein synthesis in primary cortical neurons, and assesses the neuroprotective potential of the MAP kinase interacting kinase (MNK) inhibitor, eFT508. Using expansion microscopy, we observed that 5-day exposure of low concentrations of Aβo significantly increased synapse density, particularly single synaptic boutons (SSBs) and multi-innervated spines (MIS). This finding indicates that we modelled increases in synapses characteristic of mild cognitive impairment (MCI), a transition to AD. The clinically approved MNK inhibitor eFT508 partially suppressed these synaptic alterations, restoring synapse density to control levels. While total de novo protein synthesis remained unchanged under Aβo exposure using bioorthogonal non-canonical amino acid tagging (BONCAT), subsequent proteomic profiling identified selective changes in de novo protein synthesis that are involved in synaptic function, cytoskeletal regulation, mitochondrial activity, autophagy, and the ubiquitin-proteasome system, and part of these dysregulations could be inhibited by eFT508. These findings indicate that Aβo exposure in an in vitro model of AD leads to synaptogenesis and dysregulation in de novo protein synthesis and they identify eFT508 as a compound that can counteract some of these Aβo-induced dysfunctions.