Bishara Mary A, Chum Phoebe P, Miot Fritz E L, Hooda Ankita, Hartman Richard E, Behringer Erik J
Department of Basic Sciences, Loma Linda University, Loma Linda, CA, United States.
Front Neurosci. 2025 Sep 5;19:1667585. doi: 10.3389/fnins.2025.1667585. eCollection 2025.
Alzheimer's disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset.
Dietary CBD was administered daily (80-100 mg/kg/day) in male mice and wild-type B6129SF2/J animals from 4.5 to 6.5 mo of age with inclusion of vehicle controls. RNA sequencing encompassed longitudinal and cross-sectional blood and brain samples, respectively. Metabolomics and behavioral analyses examined brain regions (cortex, hippocampus) and associated integrated neurocircuitry.
There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，涉及突触发育与维持、神经血管相互作用、离子和营养物质转运以及线粒体代谢等多种复杂紊乱。AD发病的确切分子特征以及主要病理因素仍不清楚，这给治疗开发带来了相应阻碍。本研究有两个目标，一是解析从认知障碍到AD样神经病理学发病的分子发病机制，二是研究具有神经保护作用的新型药物大麻二酚（CBD）是否会影响与AD发病相关的分子转变。
在4.5至6.5月龄的雄性小鼠和野生型B6129SF2/J动物中，每日给予膳食CBD（80 - 100毫克/千克/天），并设置溶剂对照组。RNA测序分别涵盖纵向和横断面的血液及脑样本。代谢组学和行为分析检测了脑区（皮层、海马体）及相关的整合神经回路。
有超过1000个AD发病的差异表达标志物，其中超过75%在CBD作用下表达方向被消除或逆转。信号通路包括突触发育与可塑性（如Foxp2）、神经血管相互作用（Smad9、Angptl6）、受体和离子通道（Gria4、Chrna2、Rgs7/Rgs7bp）、线粒体基因（Ndufa7、Cox7a2）、免疫（Ncr1）、氧化还原（Esr1）、脂质合成（Fasn、ApoE）以及碳水化合物代谢（Mafa、Mlxipl）。AD发病可能通过CBD治疗得到解决，它代表了神经血管相互作用、离子通道病、代谢紊乱以及发育基因异常的分子整合，涉及炎症、氧化信号传导、血脂异常和胰岛素抵抗等主要病理因素。
