Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease
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DOI：
10.1172/jci31547
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Pasinetti, Giulio Maria
中科院分区：
文献类型：
--
作者：
Wang, Jun;Ho, Lap;Pasinetti, Giulio Maria
最近的流行病学证据表明，一些抗高血压药物可能会降低阿尔茨海默病（AD）的风险。我们筛选了55个临床处方的抗高血压药物的AD-修改活动使用原代皮质海马神经元培养产生的Tg 2576 AD小鼠模型。这些药物代表了用于高血压药物治疗的所有药物类别。我们确定了7种候选抗高血压药物，可显著降低AD型P-淀粉样蛋白（A β）的蓄积。通过体外研究，我们发现只有一种候选药物缬沙坦能够减弱A β肽寡聚化为高分子量（HMW）寡聚肽，已知这与认知功能减退有关。我们发现，预防性治疗Tg 2576小鼠缬沙坦显着减少AD型神经病理和可溶性高分子量细胞外寡聚AP肽在大脑中的含量。最重要的是，缬沙坦给药还减弱了A β介导的认知恶化的发展，即使是以比用于人类高血压治疗的剂量低约2倍的剂量给药。这些临床前研究表明，某些抗高血压药物可能具有AD修饰活性，并可能在AD受试者或AD高风险受试者中预防进行性A β相关记忆缺陷。
Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type P-amyloid protein (A beta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of A beta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric AP peptides in the brain. Most importantly, valsartan administration also attenuated the development of A beta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive A beta-related memory deficits in subjects with AD or in those at high risk of developing AD.