Ryanodine receptor 2–mediated calcium leak is associated with increased glyoxalase I in the aging brain
Alzheimer disease (AD) is characterized by plaques and tangles, including calcium dysregulation and glycated products produced by reactive carbonyl compounds. AD brains have increased glyoxalase I (GLO1), a major scavenger of inflammatory carbonyl compounds, at early, but not later, stages of disease. Calcium dysregulation includes calcium leak from phosphorylated ryanodine receptor 2 (pS2808-RyR2), seen in aged macaques and AD mouse models, but the downstream consequences of calcium leak remain unclear. Here, we show that chronic calcium leak is associated with increased GLO1 expression and activity. In macaques, we found age-related increases in GLO1 expression in the prefrontal cortex (PFC), correlating with pS2808-RyR2, and localized to dendrites and astrocytes. To examine the relationship between GLO1 and RyR2, we used S2808D-RyR2 mutant mice exhibiting chronic calcium leak through RyR2, and found increased GLO1 expression and activity in the PFC and hippocampus as early as 1 month and as late as 21 months of age, with a bell-shaped aging curve. These aged S2808D-RyR2 mice demonstrated impaired working memory. As with macaques, GLO1 was expressed in astrocytes and neurons. Proteomics data generated from S2808D-RyR2 synaptosomes confirmed GLO1 upregulation. Altogether, these data suggest potential association between GLO1 and chronic calcium leak, providing resilience in early stages of aging.
Authors
- Qinyue Stacy Guan (ORCID: https://orcid.org/0000-0003-4936-8220)
- Tamás L. Horváth (ORCID: https://orcid.org/0000-0002-7522-4602)
- TuKiet T. Lam (ORCID: https://orcid.org/0000-0002-4850-3462)
- Lauren Hachmann Sansing (ORCID: https://orcid.org/0000-0002-6898-1680)
- Jonathan H. DeLong (ORCID: https://orcid.org/0000-0002-2032-8228)
- Amy F.T. Arnsten (ORCID: https://orcid.org/0000-0002-3420-1308)
- Efrat Abramson (ORCID: https://orcid.org/0000-0002-8677-4028)
- Stacy Uchendu (ORCID: https://orcid.org/0000-0001-9104-5666)
- Angus C. Nairn (ORCID: https://orcid.org/0000-0002-7075-0195)
- Jean E. Kanyo (ORCID: https://orcid.org/0000-0003-4814-7573)
- Shveta Bathla
- Elizabeth Woo (ORCID: https://orcid.org/0000-0002-7060-7575)
- Hannah E. Beatty (ORCID: https://orcid.org/0000-0002-0077-0270)
- Dibyadeep Datta (ORCID: https://orcid.org/0000-0002-5415-3067)
- Elizabeth A. Jonas (ORCID: https://orcid.org/0000-0002-1624-5999)
- Dawson C Cooper (ORCID: https://orcid.org/0000-0003-2508-0636)
- Mary Kate P. Joyce (ORCID: https://orcid.org/0000-0002-8351-0051)
- Shannon Leslie (ORCID: https://orcid.org/0000-0002-9009-6338)
- Pawel Licznerski (ORCID: https://orcid.org/0000-0003-2761-8428)
- Alison L. Herman (ORCID: https://orcid.org/0000-0002-5824-3924)
- Jiaxin Li (ORCID: https://orcid.org/0000-0002-1681-3271)
- Pinar B. Caglayan
- Ashley Kristant Albizu
Institutions
- Dartmouth College (US)
- Boston University (US)
- Johnson & Johnson (United States) (US)
- Marine Biological Laboratory (US)
- University of Michigan (US)
- W. M. Keck Foundation (US)
- Yale University (US)
- Abterra Biosciences (United States) (US)
- University of Minnesota Medical Center (US)
- University of Rochester (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-10-16
- DOI
- https://doi.org/10.1172/jci.insight.184041
- Citations
- 1
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.91
Funders
- National Institutes of Health