In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer’s mouse model

 

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• Nicotinamide riboside (3 posts to April 2016)

In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer’s mouse model

• Anshuman Swain, 
• Narayan Datt Soni, 
• Ryan B. Gaspar, 
• James G. Davis, 
• Fang Liu, 
• Halvor Juul, 
• Ravi Prakash Reddy Nanga, 
• Joseph A. Baur & 
• Ravinder Reddy 

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 We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Background

Nicotinamide adenine dinucleotide (NAD⁺) precursors, such as nicotinamide riboside (NR), have gained interest as potential therapeutics for alleviating Alzheimer’s disease (AD) pathology. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can provide insights into the effects of NR on AD by virtue of its sensitivity to monitoring the metabolic status of tissue in vivo.

Methods

This study used glutamate-weighted CEST (GluCEST) MRI to monitor glutamate-associated metabolic changes following NR treatment in the 5xFAD mouse model of AD. Drinking water was supplemented with NR or provided as is to animals over the course of expected disease progression prior to imaging experiments. Following imaging, an immunohistochemical assay to monitor the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) was performed to assess the extent of neuroinflammatory glial responses. A two-way ANCOVA with interaction was performed for statistical analysis of both CEST and IHC data.

Results

Results from GluCEST revealed significantly higher glutamate levels in the hippocampal dentate gyrus of AD mice compared to WT, with a significant reduction following treatment. GFAP staining mirrored this trend, implicating reactive astrogliosis as a mechanism for elevated glutamate. Similar patterns were observed in the cerebral peduncles, a white matter bundle, in which GFAP and Iba1 supported GluCEST findings and suggested neuroinflammation in axonal tracts. Our findings are in concordance with studies reporting elevated glutamate associated with reactive gliosis and morphological changes disrupting glutamate imbalance. Interestingly, NR restores glutamate homeostasis and alleviates neuroinflammatory processes, thus rescuing tissue from excitotoxic insults.

Conclusion

Overall, this study demonstrates the potential of NR to mitigate glutamate-driven excitotoxicity in AD pathology, and highlights GluCEST as a sensitive in vivo, clinically translatable biomarker for neuroinflammation and excitotoxicity.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AD:

Alzheimer’s disease

NR:

Nicotinamide riboside

NAM:

Nicotinamide

NAD⁺ :

Nicotinamide adenine dinucleotide

CEST:

Chemical exchange saturation transfer

MRI:

Magnetic resonance imaging

GFAP:

Glial fibrillary acidic protein

WT:

Wild–type

MT:

Magnetization transfer

APT:

Amide proton transfer

rNOE:

Relayed nueclar Overhauser effect

ANOVA:

Analysis of variance

ANTs:

Advanced Normalization tools

Aβ:

Amyloid beta

IHC:

Immunohistochemistry

GluCEST:

Glutamate–weighted chemical exchange saturation transfer