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Preventive Effect of Betaine Against Cognitive Impairments in Amyloid β Peptide-Injected Mice Through Sirtuin1 in Hippocampus

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Abstract

In the pathophysiology of Alzheimer’s disease, the deposition of amyloid β peptide (Aβ) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. We have already reported that betaine (glycine betaine), an osmolyte and methyl donor in cells, prevents the development of cognitive impairment in mice with intracerebroventricular injection of Aβ25–35, an active fragment of Aβ, associated with oxidative stress in the hippocampus, but molecular mechanisms of betaine remain to be determined. Here, to investigate a key molecule underlying the preventive effect of betaine against cognitive impairments in Aβ25–35-injected mice, cognitive tests and qPCR assays were performed in Aβ25–35-injected mice with continuous betaine intake, in which intake was started a day before Aβ25–35 injection, and then continued for 8 days. The Aβ25–35 injection impaired short-term and object recognition memories in the Y-maze and object recognition tests, respectively. PCR assays revealed the down-regulation of Sirtuin1 (SIRT1), a NAD+-dependent deacetylase that mediates metabolic responses, in the hippocampus of Aβ25–35-injected mice, whereas betaine intake prevented memory deficits as well as the decrease of hippocampal SIRT1 expression in Aβ25–35-injected mice. Further, sirtinol, an inhibitor of the Sirtuin family, blocked the preventive effect of betaine against memory deficits. On the other hand, resveratrol, the potent compound that activates SIRT1, also prevented memory impairments in Aβ25–35-injected mice, suggesting that SIRT1 plays a causative role in the preventive effect of betaine against memory deficits caused by Aβ exposure.

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Data Availability

All data generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

Aβ:

Amyloid β peptide

AD:

Alzheimer’s disease

BGT-1:

Betaine/GABA transporter-1

CaMK2α:

CaM-kinase IIα

GAT2:

GABA transporter 2

mTOR:

Mammalian target of rapamycin

PPARɤ:

Peroxisome proliferator-activated receptor γ

PSD95:

Postsynaptic density protein 95

SIRT1:

Sirtuin1

SNAP25:

Synaptosomal associated protein 25

SOD:

Superoxide dismutase

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Acknowledgements

The authors would like to thank Dr. Takayoshi Mamiya and Mr. Hiroyuki Mizuno (Meijo University) for the technical advice and helping with data analysis regarding the behavioral assay.

Funding

This work was financially supported by the Japan Society for the Promotion of Science (JSPS) 17K08321 and 20K07076 (MH), and the International Research Center for Pathogenesis of Intractable Diseases as well as Recycle of Natural Resources; the Research Institute of Meijo University. This work was also supported by the Matching Fund Subsidy for Private Universities from MEXT in Japan, which was used to purchase the confocal laser scanning fluorescence microscope. The authors would like to thank the Division for Research of Laboratory Animals, Meijo University for their technical assistance.

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Author notes

  1. Daisuke Ibi and Sari Kondo have contributed equally to this work.

Authors and Affiliations

  1. Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya, 468-8503, Japan

    Daisuke Ibi, Sari Kondo, Ayano Ohmi, Yuya Kojima, Genki Nakasai, Rika Takaba & Masayuki Hiramatsu

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  1. Daisuke Ibi
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  2. Sari Kondo
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  3. Ayano Ohmi
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Contributions

Conceived and designed the experiments: DI, MH. Performed the experiments: SK, AO, YK. Analyzed the data: DI, GN, RT. Wrote the paper: DI, MH.

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Correspondence to Masayuki Hiramatsu.

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The authors declare that there is no conflict of interest regarding the publication of the present work.

Ethical Approval

All experimental procedures were approved by the animal ethics board of Meijo University, and followed the guidelines of the Japanese Pharmacological Society (Folia Pharmacol. Japon, 1992, 99: 35A), the Interministerial Decree of May 25th, 1987 (Ministry of Education, Japan), and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

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Ibi, D., Kondo, S., Ohmi, A. et al. Preventive Effect of Betaine Against Cognitive Impairments in Amyloid β Peptide-Injected Mice Through Sirtuin1 in Hippocampus. Neurochem Res 47, 2333–2344 (2022). https://doi.org/10.1007/s11064-022-03622-z

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