Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575.
Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575.
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DOI：
10.1186/1750-1326-4-19
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发表时间：
2009-05-06
影响因子：
15.1
通讯作者：
Bacskai BJ
中科院分区：
文献类型：
--
作者：
Garcia-Alloza M;Subramanian M;Thyssen D;Borrelli LA;Fauq A;Das P;Golde TE;Hyman BT;Bacskai BJ
γ-分泌酶复合物是预防和治疗阿尔茨海默病的主要治疗靶点。先前的研究表明，用γ-分泌酶的特异性抑制剂治疗年轻的APP小鼠可以防止新斑块的形成。尚未直接显示γ-分泌酶抑制剂治疗是否会影响现有斑块。同样，斑块附近神经元形态的改变代表斑块特异性神经毒性作用。无论治疗是否影响斑块大小，这些改变的恢复都是成功治疗的重要终点。在本研究中，我们使用多光子显微镜进行体内纵向成像，研究口服活性γ-分泌酶抑制剂LY-411575对10-11个月大的APP：PS1小鼠的影响，这些小鼠具有已确定的淀粉样蛋白病理学和神经炎异常。神经元表达的YFP允许荧光检测的形态，而斑块用甲氧基-XO 4标记。在每周一次的成像过程中，在每天（5 mg/kg）用该化合物治疗3周的活小鼠中跟踪相同鉴定的神经突和斑块。尽管LY-411575降低了血浆和大脑中的Aβ水平，但对现有斑块的大小没有影响。对斑块附近的异常神经炎弯曲或非常接近老年斑的营养不良也没有影响。我们的研究结果表明，旨在抑制Aβ生成的治疗方法逆转现有斑块的效果不如预防新斑块形成的效果，并且至少在Aβ生成受到抑制但未完全阻断的情况下，对斑块介导的神经炎异常没有影响。因此，可能需要Aβ抑制与增加淀粉样蛋白清除和/或预防神经毒性的药物联合治疗，以更有效地治疗既存病变患者。
The γ-secretase complex is a major therapeutic target for the prevention and treatment of Alzheimer's disease. Previous studies have shown that treatment of young APP mice with specific inhibitors of γ-secretase prevented formation of new plaques. It has not yet been shown directly whether existing plaques would be affected by γ-secretase inhibitor treatment. Similarly, alterations in neuronal morphology in the immediate vicinity of plaques represent a plaque-specific neurotoxic effect. Reversal of these alterations is an important endpoint of successful therapy whether or not a treatment affects plaque size. In the present study we used longitudinal imaging in vivo with multiphoton microscopy to study the effects of the orally active γ-secretase inhibitor LY-411575 in 10–11 month old APP:PS1 mice with established amyloid pathology and neuritic abnormalities. Neurons expressed YFP allowing fluorescent detection of morphology whereas plaques were labelled with methoxy-XO4. The same identified neurites and plaques were followed in weekly imaging sessions in living mice treated daily (5 mg/kg) for 3 weeks with the compound. Although LY-411575 reduced Aβ levels in plasma and brain, it did not have an effect on the size of existing plaques. There was also no effect on the abnormal neuritic curvature near plaques, or the dystrophies in very close proximity to senile plaques. Our results suggest that therapeutics aimed at inhibition of Aβ generation are less effective for reversal of existing plaques than for prevention of new plaque formation and have no effect on the plaque-mediated neuritic abnormalities, at least under these conditions where Aβ production is suppressed but not completely blocked. Therefore, a combination therapy of Aβ suppression with agents that increase clearance of amyloid and/or prevent neurotoxicity might be needed for a more effective treatment in patients with pre-existing pathology.
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DOI：
10.1093/jnen/62.2.137
发表时间：
2003-02-01
影响因子：
3.2
作者：
D'Amore, JD;Kajdasz, ST;Hyman, BT
通讯作者：
Hyman, BT
影响因子：
5.3
作者：
Comery, TA;Martone, RL;Marquis, KL
通讯作者：
Marquis, KL
影响因子：
82.9
作者：
Backskai, BJ;Kajdasz, ST;Hyman, BT
通讯作者：
Hyman, BT
DOI：
10.1097/01.jnen.0000240468.12543.af
发表时间：
2006-11-01
影响因子：
3.2
作者：
Garcia-Alloza, Monica;Dodwell, Sarah A.;Bacskai, Brian J.
通讯作者：
Bacskai, Brian J.
影响因子：
15.8
作者：
Jankowsky JL;Slunt HH;Gonzales V;Savonenko AV;Wen JC;Jenkins NA;Copeland NG;Younkin LH;Lester HA;Younkin SG;Borchelt DR
通讯作者：
Borchelt DR