The Synaptic Protein Neuroligin-1 Interacts with the Amyloid β-Peptide. Is There a Role in Alzheimer's Disease?
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Date
2011
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Abstract
Amyloid beta-peptide (A beta) is the main component of the amyloid plaques associated with Alzheimer's disease (AD). In the early steps of the disease soluble A beta 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 A beta species in AD pathology, it is important to understand the mechanism by which A beta oligomers are targeted to synaptic junction. We report here the interaction between A beta 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 A beta. Using intrinsic fluorescence and surface plasmon resonance, we found that A beta 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 A beta was observed. A beta polymerization analysis-studied by thioflavin-T assay and electron microscopy-indicated that NL-1 stabilized A beta aggregates in vitro. Moreover, NL-1 acts as a nucleating factor during the A beta aggregation process, stimulating the formation of A beta oligomers. Besides, irnmunoprecipitation assays confirm that A beta oligomers interact with NL-1 but not with NL-2. In conclusion, our results show that NL-1 interacts with A beta increasing the formation of A beta oligomers, suggesting that this interaction could triggers the targeting of A beta oligomer to the postsynaptic regions of excitatory synapses.