Babić Perhoč Ana, Kovač Diana, Homolak Jan, Virag Davor, Knezović Ana, Šalković-Petrišić Melita, Osmanović Barilar Jelena
Department of Pharmacology and Croatian Institute of Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
Institute of Emergency Medicine of Dubrovnik-Neretva County, Dubrovnik, Croatia.
J Neural Transm (Vienna). 2025 Jun 16. doi: 10.1007/s00702-025-02969-1.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, metabolic dysregulation, brain insulin resistance, and oxidative stress. Familial AD (fAD) models, like the Tg2576 mice, offer insights into early-onset AD; however, their relevance to sporadic AD remains limited. This study investigated brain insulin signalling and oxidative stress in Tg2576 mice at presymptomatic (7-month) and mild AD (12-month) stages, focusing on the hippocampus and hypothalamus. Additionally, the effects of chronic oral galactose-a proposed insulin-independent energy source-were examined. Oxidative stress parameters remained unchanged across disease progression, aging, and galactose treatment, suggesting that redox processes are not significantly impaired at early stages. Insulin signalling exhibited region- and age-dependent variations, with notable changes in the hypothalamus of 7-month-old transgenic mice. Galactose treatment reduced AMPK activation in both brain regions, potentially reflecting improved energy supply via its conversion to glucose through the Leloir pathway. By 12 months of age, hippocampal alterations became more pronounced, including reduced p70S6K activity in transgenic mice, consistent with impaired mTOR signalling in AD. Galactose modulated p70S6K activity differently based on age and genotype: it increased activity in younger wild-type mice, stimulating anabolic processes, while decreasing activity in older wild-type animals. GLUT4 expression also showed nuanced responses to aging, genotype, and galactose treatment. These results highlight the heterogeneity of AD pathophysiology and the limitations of using a single model to represent the disease. The study underscores the need for broad preclinical research to address biological variability and refine therapeutic approaches for both familial and sporadic AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为认知衰退、代谢失调、脑胰岛素抵抗和氧化应激。家族性AD（fAD）模型，如Tg2576小鼠，为早发性AD提供了见解；然而，它们与散发性AD的相关性仍然有限。本研究调查了Tg2576小鼠在症状前（7个月）和轻度AD（12个月）阶段的脑胰岛素信号传导和氧化应激，重点关注海马体和下丘脑。此外，还研究了慢性口服半乳糖（一种假定的非胰岛素依赖性能量来源）的作用。在疾病进展、衰老和半乳糖治疗过程中，氧化应激参数保持不变，这表明氧化还原过程在早期阶段没有受到显著损害。胰岛素信号传导表现出区域和年龄依赖性变化，7个月大的转基因小鼠下丘脑有明显变化。半乳糖治疗降低了两个脑区的AMPK激活，这可能反映了通过Leloir途径将其转化为葡萄糖后能量供应得到改善。到12个月大时，海马体的改变变得更加明显，包括转基因小鼠中p70S6K活性降低，这与AD中mTOR信号传导受损一致。半乳糖根据年龄和基因型对p70S6K活性有不同的调节作用：它增加年轻野生型小鼠的活性，刺激合成代谢过程，同时降低老年野生型动物的活性。GLUT4表达也显示出对衰老、基因型和半乳糖治疗的细微反应。这些结果突出了AD病理生理学的异质性以及使用单一模型来代表该疾病的局限性。该研究强调了进行广泛的临床前研究以解决生物学变异性并完善家族性和散发性AD治疗方法的必要性。
