Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition.
Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition.
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DOI：
10.1523/jneurosci.4686-08.2008
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发表时间：
2008-12-10
期刊：
影响因子：
--
通讯作者：
Zipfel GJ
中科院分区：
文献类型：
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作者：
Han BH;Zhou ML;Abousaleh F;Brendza RP;Dietrich HH;Koenigsknecht-Talboo J;Cirrito JR;Milner E;Holtzman DM;Zipfel GJ
脑血管病变在阿尔茨海默病（AD）中的作用越来越受到重视。最近的证据表明，淀粉样β肽（Aβ）-在AD的神经炎斑块中发现的相同肽-可能通过其血管活性特性发挥作用。几项研究检查了表达突变淀粉样前体蛋白（APP）且可溶性Aβ水平升高但无脑淀粉样血管病（CAA）的年轻Tg 2576小鼠。这些研究提示但不能证明可溶性Aβ可显著损害脑循环。其他研究检查了具有广泛CAA的老年Tg 2576小鼠，发现更严重的脑血管功能障碍，表明CAA可能进一步损害血管功能。在此，我们检查了年轻和老年Tg 2576小鼠的血管舒张反应，以进一步评估可溶性和不溶性Aβ对血管功能的作用。结果表明：（1）Tg 2576小鼠血管损伤的发生与年龄有关;（2）CAA的严重程度与血管反应性密切相关;（3）少量CAA即可引起血管功能的明显降低或完全丧失;（4）CAA引起的血管损伤是由于血管平滑肌细胞功能障碍而非损伤或破坏;急性Aβ耗竭可改善年轻Tg 2576小鼠的血管功能，老年Tg 2576小鼠的血管功能改善程度较低。这些结果强烈表明可溶性和不溶性Aβ均导致脑血管功能障碍，除Aβ诱导的血管完整性改变外，其他机制也是原因，抗A β治疗除了对实质淀粉样蛋白有积极作用外，还可能具有有益的血管效应。
The contributing effect of cerebrovascular pathology in Alzheimer’s Disease (AD) has become increasingly appreciated. Recent evidence suggests that amyloid-β peptide (Aβ) — the same peptide found in neuritic plaques of AD — may play a role via its vasoactive properties. Several studies have examined young Tg2576 mice expressing mutant amyloid precursor protein (APP) and having elevated levels of soluble Aβ but no cerebral amyloid angiopathy (CAA). These studies suggest but don’t prove that soluble Aβ can significantly impair the cerebral circulation. Other studies examining older Tg2576 mice having extensive CAA found even greater cerebrovascular dysfunction, suggesting that CAA is likely to further impair vascular function. Herein, we examined vasodilatory responses in young and older Tg2576 mice to further assess the roles of soluble and insoluble Aβ on vessel function. We found that 1) vascular impairment was present in both young and older Tg2576 mice; 2) a strong correlation between CAA severity and vessel reactivity exists; 3) a surprisingly small amount of CAA led to marked reduction or complete loss of vessel function; 4) CAA-induced vasomotor impairment resulted from dysfunction rather than loss or disruption of vascular smooth muscle cells; and 5) acute depletion of Aβ improved vessel function in young and to a lesser degree older Tg2576 mice. These results strongly suggest that both soluble and insoluble Aβ cause cerebrovascular dysfunction, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial vascular effects in addition to positive effects on parenchymal amyloid.