Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice

Hee Jae Lee, Soo Jin Yang, Hee Jae Lee, Soo Jin Yang

Abstract

The purpose of this study is to investigate whether nicotinamide riboside (NR) can improve inflammation and cognitive function in diabetic mice. ICR male mice were fed for 14 weeks with either high-fat chow diet (HF, 60% kcal fat) or standard chow diet (CON, 10% kcal fat). HF, streptozotocin, and nicotinamide were used to induce hyperglycemia. NR or vehicle was delivered via stomach gavage for six weeks. Oral glucose tolerance test, Y-maze test, and nest construction test were conducted before and after the NR treatment period. NR treatment induced down-regulation of NLRP3, ASC, and caspase-1. NR reduced IL-1 expression significantly by 50% in whole brains of hyperglycemic mice. Other inflammatory markers including TNF-α and IL-6 were also attenuated by NR. Brain expression of amyloid-β precursor protein and presenilin 1 were reduced by NR. In addition, NR induced significant reduction of amyloid-β in whole brains of diabetic mice. NR treatment restored hyperglycemia-induced increases in brain karyopyknosis to the levels of controls. Nest construction test showed that NR improved hippocampus functions. Spatial recognition memory and locomotor activity were also improved by NR supplementation. These findings suggest that NR may be useful for treating cognitive impairment by inhibiting amyloidogenesis and neuroinflammation.

Keywords: amyloidogenesis; cognitive impairment; neuroinflammation; nicotinamide riboside.

Conflict of interest statement

There are no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The effects of nicotinamide riboside (NR) on the nucleotide binding and oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome components and inflammatory markers in whole brains of mice. Relative gene expression of (a) NLRP3, (b) apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), (c) caspase 1 (CASP1), (d) interleukin (IL)-1, (e) tumor necrosis factor (TNF)-α, and (f) IL-6. Values represent the mean ± SEM (n = 5 per group). Values with different letters in the same variable are significantly different (p < 0.05). CON, control; HFD, high-fat diet.
Figure 2
Figure 2
The effects of nicotinamide riboside (NR) on amyloid-beta precursor protein (APP), presenilin1 (PS1), and amyloid-β in the whole brain of mice. Relative gene expression of (a) APP and (b) PS1. (c) Amyloid beta concentrations in brain were analyzed by ELISA. (d) Representative Western blot for amyloid beta and beta-actin, and their respective quantification in brain. Values represent the mean ± SEM (n = 5 per group). Values with different letters in the same variable are significantly different (p < 0.05). CON, control; HFD, high-fat diet.
Figure 3
Figure 3
Representative photographs of hematoxylin and eosin (H and E)-stained brain sections. (a) The areas examined in the brain were marked with yellow boxes. (b) H and E-stained brain sections. Original magnification 400×. Yellow arrows indicate karyopyknosis of cells. CON, control; HFD, high-fat diet; NR, nicotinamide riboside.
Figure 4
Figure 4
The effects of nicotinamide riboside (NR) on behavior tests. (a) Nest torn score and (b) total nest score were evaluated from nest construction test. (c) First choice latency, (d) latency first entrance to new zone, (e) time in start zone (%), (f) alternation triplet (%), (g) total distance, and (h) mean speed in start zone are analyzed from the Y-maze test. Values represent the mean ± SEM. Values with different letters in the same variable are significantly different (p < 0.05). CON, control; HFD, high-fat diet.

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