Betaine Attenuates Hyperhomocysteinemia-Induced Cognitive Impairment by Suppressing Oxidative Stress and Activating the PI3K/AKT/GSK-3β Pathway.

Overview

1. Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China; (X.G.); (Y.F.); (Y.Z.); (Y.Y.); (Q.X.); (P.M.); (Z.P.); (Z.L.)
2. Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China
3. School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, China

Abstract

High homocysteine levels are a key risk factor for cognitive impairment, a major public health concern in aging societies. Although betaine is known to reduce Hcy levels, its effects on hyperhomocysteinemia (hHcy)-induced cognitive impairment and the underlying mechanisms remain unclear. Here, we established an hHcy-induced cognitive impairment mouse model by feeding mice a high-methionine diet for 8 weeks, followed by betaine supplementation for 14 days. Betaine treatment attenuated hHcy-induced cognitive impairment. This improvement was accompanied by alleviation of neuropathological alterations and enhancement of antioxidant capacity. Notably, betaine suppressed reactive oxygen species (ROS) accumulation, neuronal apoptosis, and Tau hyperphosphorylation at Ser396 and Thr231 in both mouse hippocampus and HT-22 cells. Mechanistically, betaine-induced activation of the PI3K/AKT/GSK-3β pathway was effectively blocked by the PI3K inhibitor LY294002. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) alone phenocopied this activation, suggesting that ROS functions as an upstream regulator of this signaling cascade. Collectively, our data demonstrate that betaine attenuates hHcy-induced cognitive impairment by suppressing oxidative stress-driven apoptosis and Tau pathology through modulation of the PI3K/AKT/GSK-3β signaling pathway. These findings suggest that betaine may hold promise for further preclinical and clinical studies, although long-term efficacy and safety evaluations remain necessary.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE308639 — at NCBI GEO; found in “Data Availability Statement”

Data Availability Statement

The RNA-seq data for this article are available in the GEO database under accession number GSE308639 at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE308639, accessed on 25 June 2026.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 5 keywords, 4 funders, 60 references.

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This paper

Gu, X., Fu, Y., Zhao, Y., Liu, Z., Yang, Y., Xie, Q., Ma, P., Peng, Z., Liu, Z., Li, J., & Xie, J. (2026). Betaine Attenuates Hyperhomocysteinemia-Induced Cognitive Impairment by Suppressing Oxidative Stress and Activating the PI3K/AKT/GSK-3β Pathway. Antioxidants (Basel, Switzerland), 15(7), 807. https://doi.org/10.3390/antiox15070807

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