Synaptic dysfunction induced by Aβ oligomers in Alzheimer's disease: AKAP150-NFAT signalling as a molecular target

Abstract

Alzheimer's disease (AD) is the most common form of dementia worldwide and to this day no effective cure has been found. Various studies suggest that synaptic dysfunction is one of the earliest pathological events in this disease, preceding even clinical symptoms. In this regard, soluble amyloid-beta oligomers (Aβo) have been identified as neurotoxic compounds that can alter synaptic function. The aim of this study is to investigate the molecular effects of Aβo on some key components of the postsynaptic signalling complex in hippocampal neuronal cultures, focusing on the AKAP-CaN-NFAT

signalling pathway, which includes scaffolding protein AKAP79/150, phosphatase calcineurin (CaN) and transcription factor NFATc3. In this research, we observed that

Aβo reduce the expression of AKAP150 in a time-dependent manner. This reduction was not prevented by the blocking of L-type calcium channels (LTCCs), suggesting that LTCCs are not involved in Aβo-induced AKAP150 decrease. Additionally, Aβo alter the cellular localization of NFATc3 and modify dendritic distribution. Collectively, these results suggest that Aβo trigger time-dependent dynamic alterations in the AKAP-CaNNFAT complex, potentially disrupting postsynaptic organization and affecting geneexpression. Our findings support the understanding of early molecular mechanisms that

contribute to synaptic dysfunction in AD and open the possibility of identifying these compounds as therapeutical targets.