Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer\u2019s disease animal model

Hyunju Kim,Joo-Youn Cho,Hye-Sun Kim,Bora Kim

doi:10.1186/s13041-020-0565-x

Hyunju Kim, Joo-Youn Cho + Show 2 more

Open Access

https://doi.org/10.1186/s13041-020-0565-x

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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by memory loss and the presence of amyloid plaques and neurofibrillary tangles in the patients’ brains. In this study, we investigated the alterations in metabolite profiles of the hippocampal tissues from 6, 8, and 12 month-old wild-type (WT) and 5xfamiliar AD (5xFAD) mice, an AD mouse model harboring 5 early-onset familiar AD mutations, which shows memory loss from approximately 5 months of age, by exploiting the untargeted metabolomics profiling. We found that nicotinamide and adenosine monophosphate levels have been significantly decreased while lysophosphatidylcholine (LysoPC) (16:0), LysoPC (18:0), and lysophosphatidylethanolamine (LysoPE) (16:0) levels have been significantly increased in the hippocampi from 5xFAD mice at 8 months or 12 months of age, compared to those from age-matched wild-type mice. In the present study, we focused on the role of nicotinamide and examined if replenishment of nicotinamide exerts attenuating effects on the reduction in dendritic spine density in hippocampal primary neurons from 5xFAD mice. Treatment with nicotinamide attenuated the deficits in spine density in the hippocampal primary neurons derived from 5xFAD mice, indicating a potential role of nicotinamide in the pathogenesis of AD. Taken together, these findings suggest that the decreased hippocampal nicotinamide level could be linked with AD pathogenesis and be a useful therapeutic target for AD.

Highlights

Alzheimer’s disease (AD) animal models have been used to investigate pathogenic mechanisms, discover potential biomarkers, and evaluate novel treatments [1, 2]
Hippocampus metabolic profiling Untargeted metabolomics profiling of hippocampal tissues was performed in WT and 5xfamiliar AD (5xFAD) mice at three different stages (6, 8, and 12 months) (Fig. 1 a)
We have investigated whether the supplementation of nicotinamide attenuates the reduction in dendritic spine density using cultured primary neurons from the hippocampus of 5XFAD mice (Fig. 3)

Summary

Introduction

Alzheimer’s disease (AD) animal models have been used to investigate pathogenic mechanisms, discover potential biomarkers, and evaluate novel treatments [1, 2]. The disturbances in metabolites of the glycolytic pathway (glucose6-phosphate and glycerol-3-phosphate) and tricarboxylic acid (TCA) cycle (α-ketoglutarate, fumarate, and succinate) were identified in astrocytes derived from newborn 5xFAD mice [11], and pantethine treatment reduced the extent of metabolic perturbation and decreased the inflammatory processes in these astrocytes, indicating the role of altered brain energetics in the AD pathogenesis; metabolic profile analyses revealed region-specific metabolic changes in the hippocampus, cortex, cerebellum, and olfactory bulbs in APP/PS1 mice [12, 13], and metabolomics signatures, including mitochondrial dysfunction and altered energy metabolism indicated by changes in nucleotide, TCA cycle, energy transfer, neurotransmitter, and amino acid metabolic pathways, were identified in APP/PS1 mice [14]; in addition, significant changes in metabolite compositions, including accumulation of fatty acids, alterations in phospholipids and acylcarnitines related to neural membrane degradation, and impaired energy management, were observed in the hippocampus and cortex in APP/PS1 mice [13].

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