Nicolakakis Nektaria, Aboulkassim Tahar, Ongali Brice, Lecrux Clotilde, Fernandes Priscilla, Rosa-Neto Pedro, Tong Xin-Kang, Hamel Edith
Laboratory of Cerebrovascular Research, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
J Neurosci. 2008 Sep 10;28(37):9287-96. doi: 10.1523/JNEUROSCI.3348-08.2008.
Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.
越来越多的证据表明，脑血管功能障碍是阿尔茨海默病（AD）发病机制中的一个重要因素。我们使用了年龄约16个月的淀粉样前体蛋白（APP）转基因小鼠，这些小鼠表现出β淀粉样蛋白（Aβ）肽生成增加以及严重的脑血管和记忆缺陷，研究了用抗氧化剂N-乙酰-L-半胱氨酸（NAC）和tempol或过氧化物酶体增殖物激活受体γ激动剂吡格列酮进行体内治疗以挽救脑血管功能和AD神经病理学某些标志物的能力。此外，我们测试了吡格列酮使由触须刺激诱导的脑血流量（CBF）和葡萄糖摄取（CGU）受损增加正常化以及逆转莫里斯水迷宫中空间记忆缺陷的能力。所有化合物都能使分离的脑动脉的脑血管反应性完全恢复，同时调节氧化应激的蛋白质也发生变化，而不会降低脑内Aβ水平或Aβ斑块负荷。吡格列酮而非NAC能显著减轻星形胶质细胞活化，并且虽不显著但改善了皮质胆碱能神经支配减少的情况。此外，吡格列酮使CBF和CGU对神经元活动增加的反应完全正常化，但未能改善空间记忆。我们的结果首次证明，用吡格列酮进行晚期药物干预不仅能克服老年APP小鼠的脑血管功能障碍和改变的神经代谢偶联，还能对抗脑氧化应激、胶质细胞活化以及部分胆碱能去神经支配。尽管可能需要早期或联合治疗来改善认知，但这些发现明确指出吡格列酮是恢复脑血管功能和对抗几种对神经元功能有害的AD标志物的最有前景的策略。
