1The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA USA.
2Institute for Medial Engineering and Science (IMES), MIT, Cambridge, MA USA.
Commun Biol. 2019 Oct 4;2:360. doi: 10.1038/s42003-019-0599-8. eCollection 2019.
Alzheimer's disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD.
阿尔茨海默病（AD）是一种进行性神经退行性痴呆，尚无治愈方法。主要假说表明β-淀粉样蛋白（Aβ）的积累有助于神经退行性变和记忆丧失，然而，确定对 Aβ 具有早期易感性的大脑区域仍然难以捉摸。我们使用 SWITCH 对完整的大脑进行免疫标记，创建了 5XFAD 小鼠中 Aβ 沉积的时空图谱。我们报告说，皮质下记忆结构首先容易受到 Aβ 的影响，并且随着年龄的增长，聚集物在越来越复杂的网络中发展。最早的 Aβ 密度最高的部位是乳头体、隔核和海马旁回——帕佩兹记忆回路的核心区域。以前，AD 中早期的乳头体功能障碍尚未确定。我们还表明，乳头体中的 Aβ与神经元过度兴奋有关，并且使用药理学方法进行调节可以减少 Aβ 沉积。我们的数据表明，大组织体积处理技术可以增强生物学发现，并表明皮质下易感性可能是 AD 早期大脑改变的基础。
