Kynigopoulos Demos, Fella Eleni, Shahabian Lucy, Christodoulou Christiana C, Papacharalampous Revekka, Diskos Konstantinos, Vagiaki Lida Evmorfia, Sidiropoulou Kyriaki, Pipis Menelaos, Kleopa Kleopas A, Panayiotou Elena
Neuropathology Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Neuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Front Neurosci. 2025 Aug 29;19:1636624. doi: 10.3389/fnins.2025.1636624. eCollection 2025.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and cognitive decline. Increasing evidence implicates systemic metabolic dysregulation in AD pathogenesis, yet it remains unclear whether modulation of peripheral lipid and glucose metabolism can alter disease progression.
We investigated the effects of two FDA-approved metabolic agents-Alirocumab, a PCSK9 inhibitor that lowers LDL cholesterol, and Gliclazide, a sulfonylurea that enhances insulin secretion-in male 5xFAD mice, a transgenic model of AD. Animals received chronic treatment for five months. Behavioral testing, hippocampal electrophysiology, ELISA, lipidomics, and adipokine profiling were performed to assess cognitive, synaptic, and molecular outcomes.
Alirocumab significantly improved spatial working memory, restored hippocampal long-term potentiation, and normalized synaptophysin expression. Gliclazide reduced neuroinflammation and partially preserved glial and neuronal markers. Both treatments decreased amyloid burden and modulated adipokine levels, with Alirocumab elevating leptin and omentin in brain and serum. Lipidomic profiling of visceral adipose tissue revealed distinct lipid remodeling and highlighted candidate pathways linking systemic metabolism to central nervous system outcomes.
These findings demonstrate that systemic modulation of lipid and glucose metabolism can influence neurodegenerative and synaptic processes in AD. The results support metabolic interventions as a potential strategy to modify AD progression through peripheral-central metabolic crosstalk.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为突触功能障碍和认知能力下降。越来越多的证据表明全身代谢失调参与了AD的发病机制，但外周脂质和葡萄糖代谢的调节是否能改变疾病进展仍不清楚。
我们在AD转基因模型雄性5xFAD小鼠中研究了两种美国食品药品监督管理局（FDA）批准的代谢药物的作用——阿利西尤单抗（一种降低低密度脂蛋白胆固醇的前蛋白转化酶枯草溶菌素9[PCSK9]抑制剂）和格列齐特（一种增强胰岛素分泌的磺脲类药物）。动物接受了为期五个月的长期治疗。进行行为测试、海马体电生理学、酶联免疫吸附测定（ELISA）、脂质组学和脂肪因子分析，以评估认知、突触和分子水平的结果。
阿利西尤单抗显著改善了空间工作记忆，恢复了海马体长期增强效应，并使突触素表达正常化。格列齐特减轻了神经炎症，并部分保留了神经胶质细胞和神经元标志物。两种治疗均降低了淀粉样蛋白负荷并调节了脂肪因子水平，阿利西尤单抗使大脑和血清中的瘦素和网膜素升高。内脏脂肪组织的脂质组分析揭示了独特的脂质重塑，并突出了将全身代谢与中枢神经系统结果联系起来的候选途径。
这些发现表明，脂质和葡萄糖代谢的全身调节可影响AD中的神经退行性和突触过程。结果支持代谢干预作为一种通过外周-中枢代谢串扰来改变AD进展的潜在策略。
