Laboratorio de Neurobiología de la Memoria, Dto. Fisiología, Biología Molecular y Celular, Fac. Cs. Exactas y Naturales, UBA/IFIByNE, CONICET, CABA, Argentina.
Laboratorio de Neurofarmacología de los Procesos de Memoria, Cátedra de Farmacología, Fac. Farmacia y Bioquímica, UBA, CABA, Argentina.
J Alzheimers Dis. 2014;40(1):69-82. doi: 10.3233/JAD-131076.
Alzheimer's disease (AD) can be considered as a disease of memory in its initial clinical stages. Amyloid-β (Aβ) peptide accumulation is central to the disease initiation leading later to intracellular neurofibrillary tangles (NFTs) of cytoskeletal tau protein formation. It is under discussion whether different Aβ levels of aggregation, concentration, brain area, and/or time of exposure might be critical to the disease progression, as well as which intracellular pathways it activates. The aim of the present work was to study memory-related early molecular and behavioral alterations in a mouse model of AD, in which a subtle deregulation of the physiologic function of Aβ can be inferred. For this purpose we used triple-transgenic (3xTg) mice, which develop Aβ and tau pathology resembling the disease progression in humans. Memory impairment in novel object recognition task was evident by 5 months of age in 3xTg mice. Hippocampus and prefrontal cortex extra-nuclear protein extracts developed differential patterns of Aβ aggregation. ERK1/MAPK showed higher levels of cytosolic activity at 3 months and higher levels of nuclear activity at 6 months in the prefrontal cortex. No significant differences were found in JNK and NF-κB activity and in calcineurin protein levels. Finally, intra-PFC administration of a MEK inhibitor in 6-month-old 3xTg mice was able to reverse memory impairment, suggesting that ERK pathway alterations might at least partially explain memory deficits observed in this model, likely as a consequence of memory trace disruption.
阿尔茨海默病（AD）在其初始临床阶段可被视为一种记忆疾病。淀粉样β（Aβ）肽的积累是疾病起始的核心，导致随后细胞内神经原纤维缠结（NFTs）的细胞骨架 tau 蛋白形成。目前正在讨论不同聚集水平、浓度、脑区和/或暴露时间是否对疾病进展以及它激活哪些细胞内途径至关重要。本研究的目的是在 AD 小鼠模型中研究与记忆相关的早期分子和行为改变，该模型可以推断出 Aβ 生理功能的细微失调。为此，我们使用了三重转基因（3xTg）小鼠，其 Aβ和 tau 病理学类似于人类疾病的进展。3xTg 小鼠在 5 个月大时，在新物体识别任务中表现出明显的记忆障碍。海马体和前额叶皮层的核外蛋白提取物表现出不同的 Aβ聚集模式。ERK1/MAPK 在 3 个月时在前额叶皮层显示出更高的细胞质活性水平，在 6 个月时显示出更高的核活性水平。在 JNK 和 NF-κB 活性和钙调神经磷酸酶蛋白水平方面未发现显著差异。最后，在 6 个月大的 3xTg 小鼠的 PFC 内给予 MEK 抑制剂能够逆转记忆障碍，表明 ERK 途径改变至少部分解释了该模型中观察到的记忆缺陷，可能是由于记忆痕迹破坏的结果。
