{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:01:42Z","timestamp":1790053302968,"version":"4.0.1"},"reference-count":81,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gobierno Regional de Magallanes y de la Ant\u00e1rtica Chilena","award":["BIP 40042452-0"],"award-info":[{"award-number":["BIP 40042452-0"]}]},{"name":"Universidad de Magallanes","id":[{"id":"https:\/\/ror.org\/049784n50","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/049784n50","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Impaired cerebral glucose metabolism is an early and clinically relevant feature of Alzheimer\u2019s disease (AD). Amyloid-\u03b2 (A\u03b2) accumulation can further disrupt neuronal energy homeostasis, increasing metabolic and oxidative vulnerability. Objective: This study evaluated whether lipid extracts obtained from different morphological structures of the Patagonian macroalga could preserve neuronal glucose metabolism and viability under basal conditions and following exposure to an A\u03b21\u201342 preparation generated under established oligomer-forming conditions. Methods: Lipid extracts derived from fronds (LEFF), stipes (LEFS), and holdfasts (LEFH) were applied at an equivalent total-lipid concentration of 0.1 \u00b5g\/mL and evaluated in primary mouse hippocampal neurons and acute hippocampal slices. Neuronal viability, glucose uptake kinetics, glycolytic flux, pentose phosphate pathway activity, ATP\/ADP ratio, AMPK\u03b1 Thr172 phosphorylation, glutathione-dependent antioxidant parameters, and gene expression were assessed. Results: Among the extracts examined at the selected non-cytotoxic concentration of 0.1 \u00b5g\/mL, the holdfast-derived lipid extract (LEFH) produced the largest biological effects. LEFH attenuated A\u03b2-induced neuronal death and preserved glucose uptake, glycolytic flux, pentose phosphate pathway activity, and the ATP\/ADP ratio in A\u03b2-treated neurons. Kinetic analysis showed a significant overall difference in the apparent maximal glucose uptake rate among preparations (p = 0.019), with LEFH displaying the highest value, whereas the apparent Michaelis\u2013Menten constant did not differ significantly among groups. LEFH also increased AMPK\u03b1 Thr172 phosphorylation and Ppargc1a mRNA expression, supporting the engagement of an AMPK-associated metabolic response. In addition, LEFH increased intracellular glutathione content and glutathione peroxidase activity under basal conditions and selectively reduced Il6 mRNA expression, whereas Tnf mRNA remained unchanged. The principal effects on glucose uptake and cellular energy status were reproduced in A\u03b2-exposed hippocampal slices. Conclusions: These findings identify the LEFH of M. pyrifera as a bioactive marine preparation capable of attenuating A\u03b2-associated neuronal metabolic dysfunction. The results support a coordinated response involving glucose utilization, energy sensing, basal glutathione-associated parameters, and metabolic gene expression. Further chemical characterization, mechanistic validation, and chronic in vivo studies are required to identify the active components and establish their translational relevance.<\/jats:p>","DOI":"10.3390\/ph19091489","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Holdfast-Derived Lipid Extract from the Patagonian Macroalga Macrocystis pyrifera Attenuates Amyloid-\u03b2-Induced Neuronal Metabolic Dysfunction In Vitro and Ex Vivo"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1054-0743","authenticated-orcid":false,"given":"Fabio","family":"M\u00e9ndez","sequence":"first","affiliation":[{"name":"Laboratorio de Ecosistemas Marinos Ant\u00e1rticos y Subant\u00e1rticos (LEMAS), Facultad de Ciencias, Universidad de Magallanes, Punta Arenas 6210427, Chile"},{"name":"Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7796-8982","authenticated-orcid":false,"given":"Pedro","family":"Cisternas","sequence":"additional","affiliation":[{"name":"Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas 6210427, Chile"},{"name":"N\u00facleo de Investigaci\u00f3n en Nutrici\u00f3n y Ciencias Alimentarias (NINCAL), Facultad de Salud y Ciencias Sociales, Universidad de las Am\u00e9ricas, Santiago 7500658, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1160-8463","authenticated-orcid":false,"given":"Paulina","family":"Ormazabal","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Lota 2465, Providencia, Santiago 7510157, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Gherardelli","sequence":"additional","affiliation":[{"name":"Mitchell Center for Alzheimer\u2019s Disease and Related Brain Disorders, Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-273X","authenticated-orcid":false,"given":"M\u00e1ximo","family":"Frangopulos","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n GAIA-Ant\u00e1rtica (CIGA), Universidad de Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3505-7018","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Mansilla","sequence":"additional","affiliation":[{"name":"Laboratorio de Ecosistemas Marinos Ant\u00e1rticos y Subant\u00e1rticos (LEMAS), Facultad de Ciencias, Universidad de Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nibaldo C.","family":"Inestrosa","sequence":"additional","affiliation":[{"name":"Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Escuela de Medicina, Universidad de Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejphar.2004.02.052","article-title":"Cerebral Glucose Metabolism in Diabetes Mellitus","volume":"490","author":"McCall","year":"2004","journal-title":"Eur. 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