Seidel Florine, Morrison Martine C, Arnoldussen Ilse, Verweij Vivienne, Attema Joline, de Ruiter Christa, van Duyvenvoorde Wim, Snabel Jessica, Geenen Bram, Franco Ayla, Wiesmann Maximilian, Kleemann Robert, Kiliaan Amanda J
Department Medical Imaging, Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 21N, 6525 EZ, Nijmegen, the Netherlands.
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Sylviusweg 71, 2333 BE, Leiden, the Netherlands.
Brain Behav Immun Health. 2025 Apr 15;45:100991. doi: 10.1016/j.bbih.2025.100991. eCollection 2025 May.
Obesity in mid-adulthood has been suggested to promote brain aging and is associated with progressive cognitive impairment later in life. However, the structural and functional alterations that underlie obesity-related cognitive dysfunction are still poorly understood, partly owing to the lack of translational models replicating age- and obesity-related brain pathology.
The effect of age and high-fat diet (HFD)-induced obesity was investigated in adult Ldlr-/-.Leiden mice, an established translational model for obesity and its comorbidities. During mid-adulthood, from three to eight months of age, brain structure and function (hippocampal volume, cortical thickness, white matter integrity, cerebral blood flow (CBF), resting-state functional connectivity) were monitored with brain magnetic resonance imaging, and cognitive function was evaluated using cognitive tests. Brain pathology was further examined with histopathological and gene expression analyses.
Ldlr-/-.Leiden mice showed age-related decreases in cortical thickness, CBF, brain connectivity, and neurogenesis along with the development of neuroinflammation and (short-term) memory impairments. On HFD feeding, Ldlr-/-.Leiden mice exhibited similar features, but memory deficits started at a younger age than in chow-fed mice. HFD-fed mice additionally showed a rise in CBF with concomitant decline in fractional anisotropy in white matter tracts. Analyses of hippocampal gene expression further revealed an age-related suppression of processes related to metabolic and neuronal function while HFD feeding strongly activated neuroinflammatory pathways.
Ldlr-/-.Leiden mice show similar critical age-related changes in brain structure and function as observed in humans. In this mouse model, HFD feeding particularly trigger disturbances in brain blood perfusion and white matter tract integrity, which may underlie an accelerated cognitive decline in obesity.
中年肥胖被认为会促进大脑衰老，并与晚年渐进性认知障碍相关。然而，肥胖相关认知功能障碍背后的结构和功能改变仍知之甚少，部分原因是缺乏复制与年龄和肥胖相关脑病理学的转化模型。
在成年Ldlr-/-。莱顿小鼠中研究年龄和高脂饮食（HFD）诱导的肥胖的影响，该小鼠是一种既定的肥胖及其合并症的转化模型。在成年中期，从三个月到八个月大，用脑磁共振成像监测脑结构和功能（海马体积、皮质厚度、白质完整性、脑血流量（CBF）、静息态功能连接），并使用认知测试评估认知功能。通过组织病理学和基因表达分析进一步检查脑病理学。
Ldlr-/-。莱顿小鼠随着神经炎症和（短期）记忆障碍的发展，皮质厚度、CBF、脑连接性和神经发生出现与年龄相关的下降。喂食HFD时，Ldlr-/-。莱顿小鼠表现出类似特征，但记忆缺陷比喂食普通饲料的小鼠出现得更早。喂食HFD的小鼠还显示CBF升高，同时白质束的各向异性分数下降。海马基因表达分析进一步揭示，与代谢和神经元功能相关的过程受到与年龄相关的抑制，而喂食HFD会强烈激活神经炎症途径。
Ldlr-/-。莱顿小鼠在脑结构和功能方面表现出与人类相似的关键年龄相关变化。在这个小鼠模型中，喂食HFD尤其会引发脑血流灌注和白质束完整性的紊乱，这可能是肥胖中认知加速衰退的基础。
