血管紧张素 II 抑制药物对阿尔茨海默病三转基因小鼠模型神经元内 Aβ 或寡聚 Aβ 水平没有影响。
Angiotensin II-inhibiting drugs have no effect on intraneuronal Aβ or oligomeric Aβ levels in a triple transgenic mouse model of Alzheimer's disease.
出版信息
Am J Transl Res. 2011 Feb;3(2):197-208. Epub 2011 Feb 5.
BACKGROUND
Reducing the excessive accumulation of amyloid β-protein (Aβ) in Alzheimer's disease (AD) is a key objective of most AD therapies. Several studies suggest that pharmacological inhibition of angiotensin-converting enzyme (ACE) or its by-product angiotensin II may delay onset or progression of dementia and it has been suggested that this occurs via regulation of Aβ. Intraneuronal oligomeric accumulation of Aβ is postulated to be one of the earliest pathological events. Thus this study investigated the effect of an ACE-inhibitor, captopril, and two angiotensin II receptor blockers (ARBs), eprosartan and valsartan, on intraneuronal Aβ pathology and oligomeric Aβ levels in a triple transgenic (3xTGAD) mouse model of AD.
METHODS
Male, adult (3-4 month old) 3xTgAD mice (n=39) were randomly assigned to 4 treatment groups: valsartan (0.17g/l), eprosartan (0.8g/l), captopril (5g/l) or normal drinking water and the drugs given ad libitum for 2 months. Mean arterial blood pressure (MABP) was measured at baseline, at 2 weeks and at 2 months when the mice were sacrificed and the brains hemisected for analysis. One hemisphere was processed for Aβ and amyloid precursor protein (APP) immunohistochemistry and the other for biochemical measurement of oligomeric Aβ and APP. ACE activity was measured in the brain and kidney.
RESULTS
MABP was significantly reduced at 2 weeks and 2 months in the ACE-I group (p=0.0006) but was unaltered in the ARB groups compared to vehicle. Neither ACE-I nor ARB treatment altered Aβ and APP immunolabelling or the level of Aβ or APP in brain tissue homogenates. Similarly neither ACE-I nor ARB treatment altered ACE activity in either brain or kidney compared to control tissue.
CONCLUSIONS
ACE-I or ARB administration over 2 months did not affect APP levels or either intraneuronal Aβ or oligomeric Aβ levels in 3xTGAD mice. While ARBs did not alter MABP, captopril did mediate reductions in MABP in the 3xTGAD mice which appeared to be independent of ACE activity. Further studies are needed to examine the effects of these drugs over a longer term and in older mice (i.e. when AD-like changes are more pronounced).
背景
减少阿尔茨海默病（AD）中淀粉样β蛋白（Aβ）的过度积累是大多数 AD 治疗的关键目标。几项研究表明，血管紧张素转换酶（ACE）或其副产物血管紧张素 II 的药理学抑制作用可能会延迟痴呆的发作或进展，并且有人认为这是通过 Aβ的调节来实现的。Aβ的细胞内寡聚体积累被假定为最早的病理事件之一。因此，本研究在 AD 的三转基因（3xTGAD）小鼠模型中，研究了 ACE 抑制剂卡托普利和两种血管紧张素 II 受体阻滞剂（ARB）厄贝沙坦和缬沙坦对细胞内 Aβ病理学和寡聚 Aβ水平的影响。
方法
雄性，成年（3-4 月龄）3xTgAD 小鼠（n=39）随机分为 4 个治疗组：缬沙坦（0.17g/l）、厄贝沙坦（0.8g/l）、卡托普利（5g/l）或正常饮用水，自由饮用 2 个月。在基线、2 周和 2 个月时测量平均动脉血压（MABP），然后处死小鼠，对半脑进行分析。一半脑用于 Aβ和淀粉样前体蛋白（APP）免疫组织化学分析，另一半脑用于寡聚 Aβ和 APP 的生化测量。测量大脑和肾脏中的 ACE 活性。
结果
ACE-I 组在 2 周和 2 个月时 MABP 显著降低（p=0.0006），而 ARB 组与对照组相比 MABP 无变化。与对照组相比，ACE-I 或 ARB 治疗均未改变 Aβ和 APP 的免疫标记或脑组织匀浆中 Aβ或 APP 的水平。同样，ACE-I 或 ARB 治疗与对照组织相比，均未改变大脑或肾脏中的 ACE 活性。
结论
在 3xTGAD 小鼠中，2 个月的 ACE-I 或 ARB 给药并未影响 APP 水平或细胞内 Aβ或寡聚 Aβ水平。虽然 ARB 未改变 MABP，但卡托普利介导了 3xTGAD 小鼠 MABP 的降低，这似乎与 ACE 活性无关。需要进一步的研究来检查这些药物在更长时间内和在老年小鼠（即 AD 样变化更明显时）的作用。
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