Badea Alexandra, Li Didong, Niculescu Andrei R, Anderson Robert J, Stout Jacques A, Williams Christina L, Colton Carol A, Maeda Nobuyo, Dunson David B
Department of Radiology, Duke University, Durham, NC, United States.
Department of Neurology, Duke University, Durham, NC, United States.
Front Neurosci. 2022 Jun 17;16:848654. doi: 10.3389/fnins.2022.848654. eCollection 2022.
Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer's disease, and even in cognitively normal individuals at risk for Alzheimer's disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer's disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer's disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer's disease.
空间导航和定向正逐渐成为前驱性阿尔茨海默病甚至有患阿尔茨海默病风险的认知正常个体认知改变的有前景的标志物。不同的载脂蛋白E（APOE）基因等位基因赋予不同程度的风险。APOE2等位基因被认为具有保护作用，APOE3被视为对照，而携带APOE4是已知的阿尔茨海默病主要遗传风险因素。我们使用携带三种人源化APOE等位基因的小鼠模型，并在莫里斯水迷宫的空间记忆任务中对它们进行测试。我们引入了一种新的指标——绝对缠绕数，通过游泳路径的形状来表征空间搜索策略。我们表明该指标对噪声具有鲁棒性，并且适用于小群体样本。此外，绝对缠绕数通过APOE3携带者相对于APOE2和APOE4基因型更直的游泳路径，能更好地区分他们。最后，这个新指标支持了APOE4雌性小鼠中更高的易感性。我们假设空间记忆和导航策略的差异与脑网络的差异有关，并表明不同基因型对海马体和尾状壳核回路有不同的依赖，这表明了白质连接的作用。而且，差异在雌性中最为明显。这种从以海马体为中心到脑网络方法的转变可能为在明显疾病表现之前识别与阿尔茨海默病风险增加相关的区域开辟途径。基于空间导航策略对新型生物标志物的进一步探索可能会扩大干预的机会窗口。所提出的框架对于剖析与前驱性阿尔茨海默病认知变化相关的脆弱回路将具有重要意义。
