Dufort-Gervais_2020_Sci.Rep_10_6956

Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Abetao), but the exact synaptic components targeted by Abetao remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Abetao, and that it can modulate Abetao toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Abetao injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Abetao injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Abetao contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Abetao-driven neurodegeneration.