February 2, 2026Alzheimer s Research & Therapy0 citationsOpen Access

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

ASAnshuman SwainUniversity of the Sciences NSNarayan Datt SoniUniversity of Pennsylvania RGRyan B. GasparUniversity of Pennsylvania

Key Points

This research aims to investigate the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer’s mouse model.
Utilized glutamate-weighted CEST MRI to monitor metabolic changes in mice.
Supplemented drinking water with nicotinamide riboside during disease progression.
Conducted immunohistochemical assays for GFAP and Iba1 to assess neuroinflammation.
Performed two-way ANCOVA for statistical analysis of CEST and IHC data.
GluCEST showed higher glutamate levels in Alzheimer’s mice than wild type, with reductions post-treatment.
GFAP staining correlated with elevated glutamate levels, indicating reactive astrogliosis.
Neuroinflammatory markers Iba1 supported GluCEST findings, suggesting inflammation in axonal tracts.

Abstract

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. 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 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. 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.

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