Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
Cell Rep. 2024 Aug 27;43(8):114574. doi: 10.1016/j.celrep.2024.114574. Epub 2024 Aug 2.
A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer's disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer's donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer's.
一种流行的假说认为，神经原纤维缠结在阿尔茨海默病（AD）导致认知能力下降中起因果作用，因为缠结在解剖上与经历神经元丧失的区域相关。我们使用双光子纵向成像直接检验了这一假说，并观察了两种小鼠模型中单个神经元的命运。在任何时间点，没有缠结的神经元的死亡率是有缠结的神经元的 3 倍以上。此外，在死亡之前，它们在整个成像过程中与邻近神经元的距离增加了 20%以上。在阿尔茨海默病供体组织中不携带缠结的神经元群体中也存在类似的微观结构变化。这些数据表明，非纤维状的 tau 使神经元处于高死亡风险中，令人惊讶的是，缠结的存在降低了这种风险。此外，皮质微观结构的变化似乎比缠结状态更能预测即将发生的细胞死亡，并且是识别阿尔茨海默病中死亡神经元的有前途的工具。
