Le Cudennec C, Faure A, Ly M, Delatour B
Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire & de la Communication, CNRS UMR 8620, Université Paris-Sud, Orsay Cedex, France.
Genes Brain Behav. 2008 Feb;7 Suppl 1:83-91. doi: 10.1111/j.1601-183X.2007.00374.x.
Intracerebral amyloid-beta (Abeta) peptide deposition is considered to play a key role in Alzheimer's disease and is designated as a principal therapeutic target. The relationship between brain Abeta levels and clinical deficits remains, however, unclear, both in human patients and in animal models of the disease. The purpose of the present study was to investigate, in a transgenic mouse model of brain amyloidosis, the consequences of Abeta deposition on basic neurological functions using a longitudinal approach. Animals were phenotyped at different ages corresponding to graded neuropathological stages (from no extracellular Abeta deposition to high amyloid loads). Sensory functions were evaluated by assessing visual and olfactory abilities and did not show any effects of the amyloid precursor protein (APP) transgene. Motor functions were assessed using multiple experimental paradigms. Results showed that motor strength was considerably reduced in APP transgenic mice compared with control animals. No deficit was noted in a motor coordination test although APP transgenic mice displayed decreased locomotion on a stationary beam. Hypolocomotion was also observed in the standard open-field test. Measures of anxiety obtained in the elevated plus-maze show some evidence of hyperanxiety in 15-month-old transgenic mice. Some of the neurological impairments showed by APP mice had an early onset and worsened with progressive aging, in parallel to gradual accumulation of Abeta in brain parenchyma. Relationships between neuropathologically assessed amyloid loads and behavioral deficits were further explored, and it was observed that motor strength deficits were correlated with cortical amyloid burden.
脑内β淀粉样蛋白（Aβ）肽沉积被认为在阿尔茨海默病中起关键作用，并被指定为主要治疗靶点。然而，在人类患者和该疾病的动物模型中，脑Aβ水平与临床缺陷之间的关系仍不清楚。本研究的目的是在脑淀粉样变性转基因小鼠模型中，采用纵向研究方法探讨Aβ沉积对基本神经功能的影响。在对应于不同神经病理阶段（从无细胞外Aβ沉积到高淀粉样蛋白负荷）的不同年龄对动物进行表型分析。通过评估视觉和嗅觉能力来评估感觉功能，未发现淀粉样前体蛋白（APP）转基因有任何影响。使用多种实验范式评估运动功能。结果显示，与对照动物相比，APP转基因小鼠的运动强度显著降低。尽管APP转基因小鼠在固定横梁上的运动减少，但在运动协调测试中未发现缺陷。在标准旷场试验中也观察到运动减少。在高架十字迷宫试验中获得的焦虑测量结果显示，15个月大的转基因小鼠有一些过度焦虑的迹象。APP小鼠表现出的一些神经功能障碍发病较早，并随着年龄的增长而恶化，这与脑实质中Aβ的逐渐积累平行。进一步探讨了神经病理学评估的淀粉样蛋白负荷与行为缺陷之间的关系，观察到运动强度缺陷与皮质淀粉样蛋白负担相关。
