Therapeutic effect of human ApoA‐I‐Milano variant in aged transgenic mouse model of Alzheimer's disease

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 Aβ 40 soluble levels and elevated Aβ 40 levels in cerebrospinal fluid, without modifying insoluble brain Aβ 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 Aβ 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.