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J Neurochem. 2013 Sep;126(5):554-64. doi: 10.1111/jnc.12280. Epub 2013 May 31.

Neto1 associates with the NMDA receptor/amyloid precursor protein complex.

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University College London School of Pharmacy, London, UK.


Neuropilin tolloid-like 1 (Neto1), is a CUB domain-containing transmembrane protein that was recently identified as a novel component of the NMDA receptor complex. Here, we have investigated the possible association of Neto1 with the amyloid precursor protein (APP)695/GluN1/GluN2A and APP695/GluN1/GluN2B NMDA receptor trafficking complexes that we have previously identified. Neto1(HA) was shown to co-immunoprecipitate with assembled NMDA receptors via GluN2A or GluN2B subunits; Neto1(HA) did not co-immunoprecipitate APP695(FLAG) . Co-immunoprecipitations from mammalian cells co-transfected with APP695(FLAG) , Neto1(HA) and GluN1/GluN2A or GluN1/GluN2B revealed that all four proteins co-exist within one macromolecular complex. Immunoprecipitations from native brain tissue similarly revealed the existence of a GluN1/GluN2A or GluN2B/APP/Neto1 complex. Neto1(HA) caused a reduction in the surface expression of both NMDA receptor subtypes, but had no effect on APP695(FLAG) - or PSD-95α(c-Myc) enhanced surface receptor expression. The Neto1 binding domain of GluN2A was mapped using GluN1/GluN2A chimeras and GluN2A truncation constructs. The extracellular GluN2A domain does not contribute to association with Neto1(HA) but deletion of the intracellular tail resulted in a loss of Neto-1(HA) co-immunoprecipitation which was paralleled by a loss of association between GluN2A and SAP102. Thus, Neto1 is concluded to be a component of APP/NMDA receptor trafficking complexes.


Alzheimer's disease; NMDA receptors; Neto1; SAP102; amyloid precursor protein; post-synaptic density 95

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