Ellagic acid and its metabolites urolithins A/B ameliorate most common disease phenotypes in cellular and mouse models for lysosomal storage disorders by enhancing extracellular vesicle secretion

• Published in: Neurobiology of disease Vol. 182; p. 106141
• Main Authors: Soto-Huelin, Beatriz, Babiy, Bohdan, Pastor, Oscar, Díaz-García, Mario, Toledano-Zaragoza, Ana, Frutos, María Dolores, Espín, Juan Carlos, Tomás-Barberán, Francisco A., Busto, Rebeca, Ledesma, María Dolores
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-06-2023; Elsevier
• Subjects: Animals; Brain; Ellagic Acid - metabolism; Ellagic Acid - pharmacology; Extracellular vesicles; Extracellular Vesicles - metabolism; Lipids; Lysosomal Storage Diseases - pathology; Lysosomal storage disorders; Lysosomes - metabolism; Mice; Niemann pick; Niemann-Pick Disease, Type A - genetics; Phenotype; Polyphenols; Sphingomyelin Phosphodiesterase - genetics; Brain; ASMko; Extracellular vesicles; Uros; BMDM; LSDs; Polyphenols; SM; ASM; NPDA; EA; dhCer; NPDC; EM; DIV; LC/MS; Cer; dhSM; PC; Lysosomal storage disorders; NPC1; Niemann pick; PE; HexCer; ECV; MES; TAG; FC; LPC; MVBs
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106141

Niemann Pick diseases types A (NPDA) and C (NPDC) are lysosomal storage disorders (LSDs) leading to cognitive impairment, neurodegeneration, and early death. NPDA and NPDC have different genetic origins, being caused by mutations in the acid sphingomyelinase (ASM) or the cholesterol transport protein NPC1, respectively. However, they share a common pathological hallmark in the accumulation of lipids in the endolysosomal compartment. Here, we tested the hypothesis that polyphenols reduce lipid overload in NPD cells by enhancing the secretion of extracellular vesicles (ECVs). We show that among the polyphenols tested, the ellagic acid metabolites, urolithin A and B, were the safest and most efficient in increasing ECV secretion. They reduced levels of accumulating lipids and lysosomal size and permeabilization in cultured bone marrow-derived macrophages and neurons from ASMko and NPC1 mutant mice, which mimic NPDA and NPDC, respectively. Moreover, oral treatment with ellagic acid reduced lipid levels, ameliorated lysosomal alterations, and diminished microglia activation in the brain of NPD mice. These results support the therapeutic value of ECV secretion and polyphenols for NPDs, which may also help treat other LSDs characterized by intracellular lipid overload.
•Brain ECV contain increased amounts of intracellular accumulating lipids in mouse models for Niemann Pick diseases (NPDs)•Polyphenols enhance ECV secretion in cellular models for NPDs•Urolithins A/B enhance ECV secretion and reduce lipid storage and lysosomal anomalies in cellular models for NPDs•Oral treatment with ellagic acid ameliorates brain pathology in mouse models for NPDs