PMID- 37658433 OWN - NLM STAT- MEDLINE DCOM- 20230905 LR - 20240331 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 20 IP - 1 DP - 2023 Sep 1 TI - Atorvastatin rescues hyperhomocysteinemia-induced cognitive deficits and neuroinflammatory gene changes. PG - 199 LID - 10.1186/s12974-023-02883-x [doi] LID - 199 AB - BACKGROUND: Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID. METHODS: Wild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods. RESULTS: Atorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task. CONCLUSIONS: These data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes. CI - (c) 2023. BioMed Central Ltd., part of Springer Nature. FAU - Weekman, Erica M AU - Weekman EM AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. eweekman@iu.edu. AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. eweekman@iu.edu. FAU - Johnson, Sherika N AU - Johnson SN AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. FAU - Rogers, Colin B AU - Rogers CB AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. FAU - Sudduth, Tiffany L AU - Sudduth TL AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. FAU - Xie, Kevin AU - Xie K AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. FAU - Qiao, Qi AU - Qiao Q AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. FAU - Fardo, David W AU - Fardo DW AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. FAU - Bottiglieri, Teodoro AU - Bottiglieri T AD - Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, TX, 75204, USA. FAU - Wilcock, Donna M AU - Wilcock DM AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA. AD - Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. LA - eng GR - P30 AG072946/AG/NIA NIH HHS/United States GR - R01 NS097722/NS/NINDS NIH HHS/United States GR - 1RO1NS097722/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20230901 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - A0JWA85V8F (Atorvastatin) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0LVT1QZ0BA (Homocysteine) SB - IM MH - Animals MH - Mice MH - Atorvastatin/pharmacology/therapeutic use MH - *Hydroxymethylglutaryl-CoA Reductase Inhibitors MH - *Hyperhomocysteinemia/complications/drug therapy MH - *Cognitive Dysfunction/drug therapy/etiology MH - Cognition MH - *Alzheimer Disease MH - *Dementia, Vascular MH - Homocysteine/toxicity PMC - PMC10474691 OTO - NOTNLM OT - Astrocyte end-feet OT - Atorvastatin OT - Cholesterol OT - Hyperhomocysteinemia OT - Microglia OT - Microhemorrhages OT - Neuroinflammation OT - Vascular contributions to cognitive impairment and dementia COIS- The authors declare they have no competing interests. EDAT- 2023/09/02 05:42 MHDA- 2023/09/05 06:41 PMCR- 2023/09/01 CRDT- 2023/09/01 23:44 PHST- 2023/03/21 00:00 [received] PHST- 2023/08/28 00:00 [accepted] PHST- 2023/09/05 06:41 [medline] PHST- 2023/09/02 05:42 [pubmed] PHST- 2023/09/01 23:44 [entrez] PHST- 2023/09/01 00:00 [pmc-release] AID - 10.1186/s12974-023-02883-x [pii] AID - 2883 [pii] AID - 10.1186/s12974-023-02883-x [doi] PST - epublish SO - J Neuroinflammation. 2023 Sep 1;20(1):199. doi: 10.1186/s12974-023-02883-x.