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Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (A\u03b2) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential. Methods: This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg\/kg\/day) could reverse the AD-like disease progression in the 5\u00d7FAD mice. Results: Results showed that treatment of 5\u00d7FAD mice with DPIN improved cognition, reduced hippocampal A\u03b2 and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K\/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5\u00d7FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition. Conclusions: These findings underscore DPIN\u2019s promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.<\/jats:p>","DOI":"10.3390\/nu16234186","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T04:47:22Z","timestamp":1733287642000},"page":"4186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic Efficacy of the Inositol D-Pinitol as a Multi-Faceted Disease Modifier in the 5\u00d7FAD Humanized Mouse Model of Alzheimer\u2019s Amyloidosis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0342-1287","authenticated-orcid":false,"given":"Dina","family":"Medina-Vera","sequence":"first","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"},{"name":"Facultad de Ciencias, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica del Coraz\u00f3n\u2014CIBERCV (Enfermedades Cardiovasculares), Hospital Universitario Virgen de la Victoria, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7716-9056","authenticated-orcid":false,"given":"Antonio J.","family":"L\u00f3pez-Gambero","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"},{"name":"INSERM, Neurocentre Magendie, University of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Verheul-Campos","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3089-0983","authenticated-orcid":false,"given":"Juan A.","family":"Navarro","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"},{"name":"Facultad de Medicina, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Morelli","sequence":"additional","affiliation":[{"name":"Laboratory of Brain Aging and Neurodegeneration, Fundaci\u00f3n Instituto Leloir (IIBBA-CONICET), Av. Patricias Argentinas 435, Ciudad Aut\u00f3noma de Buenos Aires C1405BWE, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4491-2039","authenticated-orcid":false,"given":"Pablo","family":"Galeano","sequence":"additional","affiliation":[{"name":"Laboratory of Brain Aging and Neurodegeneration, Fundaci\u00f3n Instituto Leloir (IIBBA-CONICET), Av. 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Calle Johannes Kepler, 3, 29590 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3058-0635","authenticated-orcid":false,"given":"Beatriz","family":"Pacheco-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Rivera","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-8904","authenticated-orcid":false,"given":"Francisco J.","family":"Pavon-Mor\u00f3n","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica del Coraz\u00f3n\u2014CIBERCV (Enfermedades Cardiovasculares), Hospital Universitario Virgen de la Victoria, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rosell-Valle","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5795","authenticated-orcid":false,"given":"Fernando Rodr\u00edguez de","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Grupo de Neuropsicofarmacolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Unidades Cl\u00ednicas de Neurolog\u00eda y Salud Mental, 29010 M\u00e1laga, Spain"},{"name":"Andalusian Network for Clinical and Translational Research in Neurology [NEURO-RECA], 29001 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Huynh, Q.S., Elangovan, S., and Holsinger, R.M.D. (2022). 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