Amyloid-? Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization.

ABSTRACT: Alzheimer's disease (AD) is characterized by excessive production and deposition of amyloid-beta (A?) proteins as well as synapse dysfunction and loss. While soluble A? oligomers (A?Os) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with A?Os and identified a novel interaction between neurexins (NRXs) and A?Os. A?Os bind to NRXs via the N-terminal histidine-rich domain (HRD) of ?-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, A?Os diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although A?Os do not interfere with the binding of NRX1? to NLG1 or LRRTM2, time-lapse imaging revealed that A?O treatment reduces surface expression of NRX1? on axons and that this reduction depends on the NRX1? HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of ?-NRXs, but not ?-NRXs, decreases. Thus our data indicate that A?Os interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal ?-NRXs, providing molecular and mechanistic insights into how A?Os lead to synaptic pathology in AD.

SUBMITTER: Naito Y 

PROVIDER: S-EPMC5304201 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature