Midlife obesity and high adiposity are recognized as risk factors for Alzheimer's disease (AD), with visceral adipose tissue (VAT) playing a central role due to its endocrine and metabolic activity. Disturbances in VAT metabolism and adipokine secretion exacerbate AD pathology. Andrographolide (Andro), known for its anti-diabetic properties, enhances neuronal glucose uptake and alleviates AD pathology. However, its effects on VAT metabolism in AD remain unexplored. This study aimed to investigate the impact of Andro on glucose metabolism in VAT using a high-fat diet (HFD)-induced obesity model in AD mice (APP/PS1). APP/PS1 mice were fed an HFD and received Andro injections (2 mg/kg, three times a week for 16 weeks). VAT samples were analyzed for glucose uptake, glycolytic rate, pentose phosphate flux, ADP-ATP levels, gene expression, and enzymatic activity of glucose metabolic regulators. In APP/PS1 mice, HFD significantly increased glucose uptake and reduced GLUT4 expression in VAT, effects counteracted by Andro (p < 0.05). Andro-treated HFD-fed mice exhibited reduced glucose oxidation through glycolysis (p < 0.05), leading to decreased ATP production (p < 0.05). Andro administration restored the activity of key glycolytic enzymes and mitigated several HFD-induced metabolic alterations (p < 0.05). The study reveals significant metabolic changes in the VAT of obese APP/PS1 mice and highlights Andro's potential as a therapeutic agent for addressing VAT impairment induced by obesity in AD.

Emerging evidence implicates metabolic dysfunction as a key contributor to Alzheimer’s disease (AD) pathogenesis. Fructose, a major component of modern diets, promotes systemic metabolic alterations; however, its direct impact on AD-related brain dysfunction remains poorly defined. Here, we investigated the effects of short-term fructose consumption on systemic metabolism, brain glucose handling, and cognitive performance in APP/PS1 transgenic mice. Six-month-old asymptomatic male mice received 15% fructose in drinking water for eight weeks, while controls received plain water. Fructose-fed APP/PS1 mice developed metabolic alterations consistent with early metabolic syndrome, including increased fasting glucose and dyslipidemia. These changes were accompanied by reduced cerebral glucose utilization, increased Aβ₄₂ accumulation, and impaired cognitive performance. In parallel, fructose intake enhanced neuroinflammatory markers, suggesting a coordinated disruption of metabolic and inflammatory pathways in the brain. Collectively, these findings support the idea that fructose consumption may exacerbate Alzheimer-like alterations linking systemic metabolic dysfunction to impaired brain glucose metabolism and neuroinflammation. This study provides mechanistic evidence supporting a role for dietary fructose as a modifiable risk factor in AD vulnerability.

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 Aβ_1–42 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.

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the progressive loss of specific neuronal cell populations and are associated with protein aggregates. Current therapeutic approaches are still limited due to the complexity and heterogeneity of these diseases, which points toward an urgent need to discover and develop new therapeutic agents. Natural compounds are a promising source of novel bioactive agents targeting multiple mechanisms of action implicated in neurodegeneration. Andrographolide (ANDRO) is a natural compound extracted from Andrographis paniculata, a traditional Chinese herb known for its anti-inflammatory and antioxidant properties, which has emerged as a potential neuroprotective agent due to its ability to cross the blood–brain barrier (BBB). ANDRO can exert neuroprotective effects by modulating numerous transcription factors and signaling pathways across different cell types in the central nervous system (CNS). It has been described that ANDRO reverses cognitive and/or motor impairments in AD and PD study models. However, the cellular and molecular mechanisms behind these protective effects are still being elucidated. In this review, we analyze the most recent findings on ANDRO, a neuroprotective agent with multiple biological targets that could reduce the progression of the most prevalent neurodegenerative diseases, AD and PD.