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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

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Publications

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

Naito Yusuke Y Tanabe Yuko Y Lee Alfred Kihoon AK Hamel Edith E Takahashi Hideto H

Scientific reports 20170213

Alzheimer's disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) 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 AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N ...[more]

PMID: 28211900

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-? peptide (A?). Monomeric soluble A? can switch from helicoidal to ?-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. A? can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that A? nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an A? analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A? related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated A? oligomers was observed. Our results show that A? nitrotyrosination is a post-translational modification that increases A? synaptotoxicity. SIGNIFICANCE STATEMENT:We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-? (A?) favors the stabilization of highly toxic oligomers and inhibits the formation of A? fibrils. The nitrated A? oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Dataset Information

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

Publications

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

Similar Datasets

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