The synaptic protein neuroligin-1 interacts with the amyloid ß-peptide. Is there a role in Alzheimer's disease?

Amyloid ß-peptide (Aß) is the main component of the amyloid plaques associated with Alzheimer's disease (AD). In the early steps of the disease soluble Aß oligomers are produced. According to the current "amyloid hypothesis" these oligomers can accumulate over time, leading progressively to the loss of synaptic function and the cognitive failure characteristic of AD. To understand the role of oligomeric Aß species in AD pathology, it is important to understand the mechanism by which Aß oligomers are targeted to synaptic junction. We report here the interaction between Aß with neuroligin-1 (NL-1), a postsynaptic cell-adhesion protein specific for excitatory synapses, which shares a high degree of similarity with acetylcholinesterase, the first synaptic protein described to interact with Aß. Using intrinsic fluorescence and surface plasmon resonance, we found that Aß binds to the extracellular domain of NL-1 with a K(d) in the nanomolar range. In the case of NL-2, a postsynaptic cell-adhesion protein specific for inhibitory synapses, just a very weak interaction with Aß was observed. Aß polymerization analysis-studied by thioflavin-T assay and electron microscopy-indicated that NL-1 stabilized Aß aggregates in vitro. Moreover, NL-1 acts as a nucleating factor during the Aß aggregation process, stimulating the formation of Aß oligomers. Besides, immunoprecipitation assays confirm that Aß oligomers interact with NL-1 but not with NL-2. In conclusion, our results show that NL-1 interacts with Aß increasing the formation of Aß oligomers, suggesting that this interaction could triggers the targeting of Aß oligomer to the postsynaptic regions of excitatory synapses.