APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice.
APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice.
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DOI：
10.1177/0271678x231172842
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发表时间：
2023-11
影响因子：
6.3
通讯作者：
Hall, Catherine N.
中科院分区：
文献类型：
--
作者：
Bonnar, Orla;Shaw, Kira;Anderle, Silvia;Grijseels, Dori M.;Clarke, Devin;Bell, Laura;King, Sarah L.;Hall, Catherine N.
血管因素被认为是阿尔茨海默病(AD)发病的早期和重要因素，然而载脂蛋白(ApoE)基因的ε4等位基因(AD的危险因素)的作用尚不清楚。在麻醉的小鼠中，ApoE4基因与早期和严重的新皮质血管缺陷有关，但在人类中，血管和认知功能障碍集中在海马结构，出现得更晚。在临床前阶段，APOE4可能如何与血管系统相互作用来传递AD风险，这代表了现有知识的一个缺口。为了避免潜在的麻醉混乱，并探索与人类疾病最相关的区域，我们使用神经元和血管的双光子显微镜研究了清醒的APOE3和APOE4-tr小鼠的视觉皮质和海马区。我们发现轻微的血管缺陷：APOE4小鼠的血管密度和功能性充血没有受到影响，神经元或血管功能直到中年后期也没有下降。相反，在视觉刺激过程中，血管反应性降低，小动脉血管运动减少，神经元钙信号增加。这表明，单独而言，APOE4的表达并不是灾难性的，而是稳定地改变了神经血管生理学。我们认为，这种状态使APOE4携带者对随后的伤害更敏感，例如损伤或β淀粉样蛋白堆积。
Vascular factors are known to be early and important players in Alzheimer’s disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.
影响因子：
4.8
作者：
Shaw K;Boyd K;Anderle S;Hammond-Haley M;Amin D;Bonnar O;Hall CN
通讯作者：
Hall CN