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

Montse Solé*, Paula Marazuela, Laura Castellote, Anna Bonaterra-Pastra, Lydia Giménez-Llort, Mar Hernández-Guillamon*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review


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 Aβ40 soluble levels and elevated Aβ40 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.

Original languageEnglish
Pages (from-to)1999-2017
Number of pages19
JournalBritish Journal of Pharmacology
Issue number15
Publication statusPublished - Aug 2023


  • Alzheimer's disease
  • ApoA-I-Milano
  • Apolipoprotein A-I
  • beta-amyloid
  • cerebrovasculature
  • drug reprofiling
  • receptor for advanced glycation end products


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