Dinamarca_2011_Biochemistry_50_8127

Amyloid beta-peptide (Abeta) is the main component of the amyloid plaques associated with Alzheimer's disease (AD). In the early steps of the disease soluble Abeta 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 Abeta species in AD pathology, it is important to understand the mechanism by which Abeta oligomers are targeted to synaptic junction. We report here the interaction between Abeta 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 Abeta. Using intrinsic fluorescence and surface plasmon resonance, we found that Abeta 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 Abeta was observed. Abeta polymerization analysis-studied by thioflavin-T assay and electron microscopy-indicated that NL-1 stabilized Abeta aggregates in vitro. Moreover, NL-1 acts as a nucleating factor during the Abeta aggregation process, stimulating the formation of Abeta oligomers. Besides, immunoprecipitation assays confirm that Abeta oligomers interact with NL-1 but not with NL-2. In conclusion, our results show that NL-1 interacts with Abeta increasing the formation of Abeta oligomers, suggesting that this interaction could triggers the targeting of Abeta oligomer to the postsynaptic regions of excitatory synapses.