German Center for Neurodegenerative Diseases Dresden, Dresden, Germany; Center for Regenerative Therapies Technical University Dresden, Dresden, Germany; Institute of Anatomy, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
German Center for Neurodegenerative Diseases Dresden, Dresden, Germany; Center for Regenerative Therapies Technical University Dresden, Dresden, Germany.
Biol Psychiatry. 2023 Nov 1;94(9):721-731. doi: 10.1016/j.biopsych.2023.04.009. Epub 2023 Apr 17.
One-third of the risk for Alzheimer's disease is explained by environment and lifestyle, but Alzheimer's disease pathology might also affect lifestyle and thereby impair the individual potential for health behavior and prevention.
We examined in mice how the App (NL-F) knockin mutation affects the presymptomatic response to environmental enrichment (ENR) as an experimental paradigm addressing nongenetic factors. We assessed the emergence of interindividual phenotypic variation under the condition that both the genetic background and the shared environment were held constant, thereby isolating the contribution of individual behavior (nonshared environment).
After 4 months of ENR, the mean and variability of plasma ApoE were increased in NL-F mice, suggesting a presymptomatic variation in pathogenic processes. Roaming entropy as a measure of behavioral activity was continuously assessed with radiofrequency identification (RFID) technology and revealed reduced habituation and variance in NL-F mice compared with control animals, which do not carry a Beyreuther/Iberian mutation. Intraindividual variation decreased, while behavioral stability was reduced in NL-F mice. Seven months after discontinuation of ENR, we found no difference in plaque size and number, but ENR increased variance in hippocampal plaque counts in NL-F mice. A reactive increase in adult hippocampal neurogenesis in NL-F mice, known from other models, was normalized by ENR.
Our data suggest that while NL-F has early effects on individual behavioral patterns in response to ENR, there are lasting effects on cellular plasticity even after the discontinuation of ENR. Hence, early behavior matters for maintaining individual behavioral trajectories and brain plasticity even under maximally constrained conditions.
阿尔茨海默病的风险有三分之一可归因于环境和生活方式，但阿尔茨海默病的病理变化也可能影响生活方式，从而损害个人健康行为和预防的潜力。
我们在小鼠中研究了 App（NL-F）敲入突变如何影响环境丰富（ENR）的无症状前反应，作为一种解决非遗传因素的实验范例。我们评估了个体行为（非共享环境）在遗传背景和共享环境保持不变的情况下出现个体间表型变异的情况。
在 ENR 4 个月后，NL-F 小鼠的血浆 ApoE 平均值和变异性增加，表明致病过程出现无症状前变化。作为行为活动的衡量标准，漫游熵通过射频识别（RFID）技术进行连续评估，与不携带 Beyreuther/Iberian 突变的对照动物相比，NL-F 小鼠的习惯化和变异性降低。NL-F 小鼠的个体内变异性降低，行为稳定性降低。在停止 ENR 7 个月后，我们发现斑块大小和数量没有差异，但 ENR 增加了 NL-F 小鼠海马斑块计数的变异性。NL-F 小鼠中的成年海马神经发生的反应性增加，这是其他模型所已知的，通过 ENR 得到了正常化。
我们的数据表明，虽然 NL-F 对 ENR 反应的个体行为模式有早期影响，但即使在停止 ENR 后，对细胞可塑性仍有持久影响。因此，即使在最大程度受限的条件下，早期行为对于维持个体行为轨迹和大脑可塑性也很重要。
