Novel interaction between Alzheimer\u2019s disease-related protein presenilin 1 and glutamate transporter 1

Katarzyna Marta Zoltowska,Oksana Berezovska,Masato Maesako,Joshua Meier

doi:10.1038/s41598-018-26888-2

Abstract

Neuronal hyperactivity is one of the earliest events observed in Alzheimer’s disease (AD). Moreover, alterations in the expression of glutamate transporters have been reported to exacerbate amyloid pathology and cognitive deficits in transgenic AD mouse models. However, the molecular links between these pathophysiological changes remain largely unknown. Here, we report novel interaction between presenilin 1 (PS1), the catalytic component of the amyloid precursor protein-processing enzyme, γ-secretase, and a major glutamate transporter-1 (GLT-1). Our data demonstrate that the interaction occurs between PS1 and GLT-1 expressed at their endogenous levels in vivo and in vitro, takes place in both neurons and astrocytes, and is independent of the PS1 autoproteolysis and γ-secretase activity. This intriguing discovery may shed light on the molecular crosstalk between the proteins linked to the maintenance of glutamate homeostasis and Aβ pathology.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized neuropathologically by progressive formation of intracellular neurofibrillary tangles (NFTs), extracellular amyloid β (Aβ) plaques and synaptic dysfunctions
It has been recently reported that presenilin 1 (PS1) may be involved in the modulation of neurotransmitter release at the synapse via direct interaction with ryanodine receptors (RyR)[37] and synaptic vesicle release machinery protein, synaptotagmin 1, in neurons[31,33]
We report the discovery of the PS1 interaction with the glutamate transporter glutamate transporter-1 (GLT-1) in both neurons and astrocytes, which may suggest a novel role of PS1 in regulation of the glutamate uptake

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized neuropathologically by progressive formation of intracellular neurofibrillary tangles (NFTs), extracellular amyloid β (Aβ) plaques and synaptic dysfunctions. Clinical observations suggest that familial AD (fAD) patients, including those with presenilin 1 (PS1) mutations, may have higher incidence of epileptic seizures[15] and that individuals diagnosed with epilepsy in childhood present more severe amyloid plaque deposition as middle-aged adults[16]. These observations hint towards the potential cross-talk between PS1/amyloid deposition and hyperactivity/Glu dyshomeostasis in the brain. GLT-1, GLT1a, expression and activity have been demonstrated in neurons, where it plays an important role in axonal glutamate uptake[17,20,21,22,23]. The current study reveals a molecular link between PS1 and GLT-1, presenting a rationale for further evaluation of the PS1-GLT-1 binding as potential novel therapeutic target

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Conclusion