Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood–Brain Barrier Failure

Damian M Cummings,Angelo Tedoldi,Lion Shahab,Sebastian Brandner,Christina E Murray,Dervis A Salih,Tiffanie A Benway,Angela Richard-Loendt,Frances A Edwards,Monica M Fernandes Freitas,Tammaryn Lashley,Hinze Ho

doi:10.1093/cercor/bhx046

Abstract

Neuronal pentraxin 1 (NPTX1) has been implicated in Alzheimer's disease, being present in and around dystrophic neurons in plaques, affecting glutamatergic transmission postsynaptically and mediating effects of amyloidβ. Here, we confirm the presence of NPTX1 around plaques in postmortem Alzheimer's disease brain and report that acutely applied human NPTX1 increases paired-pulse ratio at mouse CA3-CA1 hippocampal synapses, indicating a decrease in glutamate release. In contrast, chronic exposure to NPTX1, NPTX2, or NPTX receptor decreases paired-pulse ratio, mimicking some of the earliest changes in mice expressing familial Alzheimer's disease genes. The peripheral pentraxin, serum amyloid P component (SAP), causes similar synaptic effects to NPTX1. The presence of SAP on amyloid plaques in Alzheimer's disease confirms that it can enter the brain. We show that SAP and neuronal pentraxins can interact and that SAP can enter the brain if the blood-brain barrier is compromised, suggesting that peripheral pentraxins could affect central synaptic transmission via this interaction, especially in the event of blood-brain barrier breakdown.

Highlights

Several members of the pentraxin family, the neuronal pentraxins 1 (NPTX1), 2 (NPTX2, known as neuronal activity regulated pentraxin, NARP), and the neuronal pentraxin receptor (NPTXR) are expressed in neurons of the central nervous system (Schlimgen et al 1995; Tsui et al 1996), where, under normal physiological conditions, they modulate synaptic transmission
We demonstrate here for the first time that all 3 NPTXs and the peripheral pentraxin serum amyloid P component (SAP) have effects presynaptically, strongly decreasing paired-pulse ratio when added to the culture medium of organotypic slices over a 7-day period
When Neuronal pentraxin 1 (NPTX1) or SAP was added acutely, the opposite effect was seen with an increase of paired-pulse ratio, suggesting that the direct effect of the pentraxins is a decrease in probability of evoked glutamate release

Summary

Introduction

Several members of the pentraxin family, the neuronal pentraxins 1 (NPTX1), 2 (NPTX2, known as neuronal activity regulated pentraxin, NARP), and the neuronal pentraxin receptor (NPTXR) are expressed in neurons of the central nervous system (Schlimgen et al 1995; Tsui et al 1996), where, under normal physiological conditions, they modulate synaptic transmission. The membrane-bound form can be cleaved enzymatically to release a diffusible form (Kirkpatrick et al 2000). These 3 pentraxins have effects on postsynaptic glutamate receptors, with NPTX2 alone or in a complex with NPTX1 and NPTXR enhancing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor clustering in excitatory synapses, including those onto parvalbumin-positive interneurons (O’Brien et al 1999; Xu et al 2003; Chang et al 2010; Pelkey et al 2015). Amyloidβ-induced increase in NPTX1 expression has been implicated in neuronal toxicity (Abad et al 2006)

Methods

Results

Conclusion