Abstract
Background: Impaired cerebral glucose metabolism is an early and clinically relevant feature of Alzheimer’s disease (AD). Amyloid-β (Aβ) 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 Aβ1–42 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 µg/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, AMPKα 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 µg/mL, the holdfast-derived lipid extract (LEFH) produced the largest biological effects. LEFH attenuated Aβ-induced neuronal death and preserved glucose uptake, glycolytic flux, pentose phosphate pathway activity, and the ATP/ADP ratio in Aβ-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–Menten constant did not differ significantly among groups. LEFH also increased AMPKα 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 Aβ-exposed hippocampal slices. Conclusions: These findings identify the LEFH of M. pyrifera as a bioactive marine preparation capable of attenuating Aβ-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.