LOW-DOSE ABETA OLIGOMERS INDUCE ABERRANT SYNAPTOGENESIS AND PROTEOME REMODELLING RESCUED BY CLINICALLY APPROVED MNK1/2 INHIBITOR EFT508

Alzheimer’s disease (AD) is characterized by early synaptic dysregulation and impaired proteostasis, processes strongly influenced by amyloid-β oligomers (Aβo). At prodromal stages such as mild cognitive impairment (MCI), increases in synapse number are often observed. eFT508 (tomivosertib), a clinically approved, selective MNK1/2 inhibitor that reduces aberrant eIF4E-dependent translation, has emerged as a potential modulator of protein homeostasis. Here, we investigated how prolonged exposure to low concentrations of rat Aβo (100 nM) affects synaptic architecture and de novo protein synthesis in rat primary cortical neurons, and whether eFT508 can rescue these alterations. Using expansion microscopy, we found that 5-day Aβo exposure significantly increased synapse density, in particular single synaptic boutons (SSBs) and multi-innervated spines (MIS). These structural changes resemble the excessive synaptogenesis reported during early MCI. Notably, eFT508 partially reversed these effects, restoring SSB density to control levels. Global de novo protein synthesis assessed by Bioorthogonal Non-canonical Amino acid Tagging (BONCAT) was unchanged after 5-day Aβo treatment. However, proteomic analysis of newly synthesized proteins revealed selective dysregulation in pathways linked to synaptic function, cytoskeletal dynamics, mitochondrial processes, autophagy, and the ubiquitin–proteasome system. A subset of these Aβo-induced alterations was attenuated by eFT508. APP is one of the proteins produced through local translation, which may cause the increased synaptogenesis. In summary, our findings demonstrate that low-level Aβo exposure induces selective synapse formation and targeted disturbances in protein synthesis and identify eFT508 as a promising target of mitigating early AD-related synaptic dysfunctions.