Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Department of Neuropathology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Sci Rep. 2019 Feb 26;9(1):2827. doi: 10.1038/s41598-019-39494-7.
Epidemiological studies have shown that atherosclerotic risk factors accelerate the pathological process underlying Alzheimer's disease (AD) via chronic cerebral hypoperfusion. In this study, we aimed to clarify the mechanisms by which cerebral hypoperfusion may exacerbate AD pathology. We applied bilateral common carotid artery stenosis (BCAS) to a mice model of AD and evaluated how the equilibrium of amyloid β oligomers respond to hypoperfusion. BCAS accelerated amyloid β (Aβ) convergence to the aggregation seed, facilitating the growth of Aβ plaques, but without changing the total Aβ amount in the brain. Furthermore, Aβ oligomers with high molecular weight increased in the brain of BCAS-operated mice. Considering Aβ is in an equilibrium among monomeric, oligomeric, and aggregation forms, our data suggest that cerebral hypoperfusion after BCAS shifted this equilibrium to a state where a greater number of Aβ molecules participate in Aβ assemblies to form aggregation-prone Aβ oligomers with high molecular weight. The reduced blood flow in the cerebral arteries due to BCAS attenuated the dynamics of the interstitial fluid leading to congestion, which may have facilitated Aβ aggregation. We suggest that cerebral hypoperfusion may accelerate AD by enhancing the tendency of Aβ to become aggregation-prone.
流行病学研究表明，动脉粥样硬化危险因素通过慢性脑灌注不足加速了阿尔茨海默病（AD）的病理过程。在这项研究中，我们旨在阐明脑灌注不足可能加剧 AD 病理的机制。我们应用双侧颈总动脉狭窄（BCAS）建立 AD 小鼠模型，并评估脑灌注不足如何影响淀粉样β寡聚体的平衡。BCAS 加速了淀粉样β（Aβ）向聚集种子的聚集，促进了 Aβ斑块的生长，但不改变大脑中的总 Aβ量。此外，BCAS 手术小鼠大脑中高分子量的 Aβ寡聚体增加。鉴于 Aβ在单体、寡聚体和聚集形式之间处于平衡状态，我们的数据表明，BCAS 后的脑灌注不足将这种平衡状态转变为更多的 Aβ分子参与 Aβ组装，形成易聚集的高分子量 Aβ寡聚体。BCAS 导致脑动脉血流减少，导致间质液动力学减弱，从而导致充血，可能促进了 Aβ聚集。我们认为，脑灌注不足可能通过增强 Aβ的聚集倾向加速 AD 的发生。
