Ouabain Ameliorates Alzheimer's Disease-Associated Neuropathology and Cognitive Impairment in FAD ^4T Mice.

Publisher: MDPI Publishing Country of Publication: Switzerland NLM ID: 101521595 Publication Model: Electronic Cited Medium: Internet ISSN: 2072-6643 (Electronic) Linking ISSN: 20726643 NLM ISO Abbreviation: Nutrients Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI Publishing

Alzheimer Disease*/drug therapy ; Alzheimer Disease*/metabolism ; Cognitive Dysfunction*/drug therapy ; Cognitive Dysfunction*/metabolism ; Mice, Transgenic* ; Disease Models, Animal* ; Ouabain*/pharmacology; Animals ; Mice ; Signal Transduction/drug effects ; Humans ; Membrane Glycoproteins/metabolism ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/metabolism ; Receptors, Immunologic/genetics ; Amyloid beta-Peptides/metabolism ; Microglia/drug effects ; Microglia/metabolism ; Male ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism

Background: Alzheimer's disease (AD) is a common clinical neurodegenerative disorder, primarily characterized by progressive cognitive decline and behavioral abnormalities. The hallmark pathological changes of AD include widespread neuronal degeneration, plaques formed by the deposition of amyloid β-protein (Aβ), and neurofibrillary tangles (NFTs). With the acceleration of global aging, the incidence of AD is rising year by year, making it a major global public health concern. Due to the complex pathology of AD, finding effective interventions has become a key focus of research. Ouabain (OUA), a cardiac glycoside, is well-known for its efficacy in treating heart disease. Recent studies have also indicated its potential in AD therapy, although its exact mechanism of action remains unclear. Methods: This study integrates bioinformatics, multi-omics technologies, and in vivo and in vitro experiments to investigate the effects of OUA on the pathophysiological changes of AD and its underlying molecular mechanisms. Results: This study analyzed the expression of the triggering receptor expressed on myeloid cells 2 (TREM2) across different stages of AD using bioinformatics. Serum samples from patients were used to validate soluble TREM2 (sTREM2) levels. Using an Aβ 1-42 -induced microglial cell model, we confirmed that OUA enhances the PI3K/AKT signaling pathway activation by upregulating TREM2, which reduces neuroinflammation and promotes the transition of microglia from an M1 proinflammatory state to an M2 anti-inflammatory state. To evaluate the in vivo effects of OUA, we assessed the learning and memory capacity of FAD ^4T transgenic mice using the Morris water maze and contextual fear conditioning tests. We used real-time quantitative PCR, immunohistochemistry, and Western blotting to measure the expression of inflammation-associated cytokines and to assess microglia polarization. OUA enhances cognitive function in FAD ^4T mice and has been confirmed to modulate microglial M1/M2 phenotypes both in vitro and in vivo. Furthermore, through bioinformatics analysis, molecular docking, and experimental validation, TREM2 was identified as a potential target for OUA. It regulates PI3K/Akt signaling pathway activation, playing a crucial role in OUA-mediated M2 microglial polarization and its anti-inflammatory effects in models involving Aβ 1-42 -stimulated BV-2 cells and FAD ^4T mice. Conclusions: These findings indicate that OUA exerts anti-neuroinflammatory effects by regulating microglial polarization, reducing the production of inflammatory mediators, and activating the PI3K/Akt signaling pathway. Given its natural origin and dual effects on microglial polarization and neuroinflammation, OUA emerges as a promising therapeutic candidate for neuroinflammatory diseases such as AD.

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52072360, 62305347 National Natural Science Foundation of China

Keywords: Alzheimer’s disease; TREM2; cognitive impairment; microglia; ouabain

5ACL011P69 (Ouabain)
0 (Membrane Glycoproteins)
0 (Receptors, Immunologic)
0 (Trem2 protein, mouse)
0 (Amyloid beta-Peptides)
EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)

Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241028

20241028

PMC11510559

10.3390/nu16203558

39458551