| First Author | Solé M | Year | 2023 |
| Journal | Br J Pharmacol | Volume | 180 |
| Issue | 15 | Pages | 1999-2017 |
| PubMed ID | 36872299 | Mgi Jnum | J:349615 |
| Mgi Id | MGI:7642096 | Doi | 10.1111/bph.16065 |
| Citation | Sole M, et al. (2023) Therapeutic effect of human ApoA-I-Milano variant in aged transgenic mouse model of Alzheimer's disease. Br J Pharmacol 180(15):1999-2017 |
| abstractText | BACKGROUND AND PURPOSE: Therapies based on apolipoprotein A-I (ApoA-I), classically tested for cardiovascular diseases, were recently proposed for Alzheimer's disease (AD). Based on a drug reprofiling approach, our objective was to explore the use of a natural variant of ApoA-I form, ApoA-I-Milano (M), as a treatment for AD. ApoA-I-M contains the R173C mutation, and confers protection against atherosclerosis development, although ApoA-I-M carriers exhibit low HDL levels. EXPERIMENTAL APPROACH: Middle-aged (12-month-old) and aged (21-month-old) APP23 mice were intraperitoneally treated for 10 weeks with human recombinant ApoA-I-M (hrApoA-I-M) protein or saline. Pathology progression through behavioural parameters and biochemical determinations was evaluated. KEY RESULTS: In middle-aged group, hrApoA-I-M treatment reduced the anxiety behaviour associated with this AD model. In aged mice, hrApoA-I-M reversed T-Maze performance alterations, a cognitive improvement accompanied by neuronal loss recovery in the dentate gyrus. Aged mice treated with hrApoA-I-M showed lower brain Abeta(40) soluble levels and elevated Abeta(40) levels in cerebrospinal fluid, without modifying insoluble brain Abeta burden. Interestingly, hrApoA-I-M sub-chronic treatment induced a molecular effect on the cerebrovasculature, increasing occludin expression and ICAM-1 presence, as well as promoting an elevation of plasma soluble RAGE in all hrApoA-I-M-treated mice, drastically decreasing the AGEs/sRAGE ratio, a marker of endothelial damage. CONCLUSION AND IMPLICATIONS: Peripheral hrApoA-I-M treatment shows a beneficial impact on working memory, involving mechanisms related with brain Abeta mobilization and modulation of the levels of cerebrovascular markers. Our study shows the potential therapeutic applicability of a safe and non-invasive treatment based on peripheral administration of hrApoA-I-M in AD. |
