Correction of microtubule defects within Aβ plaque-associated dystrophic axons results in lowered Aβ release and plaque deposition.
Correction of microtubule defects within Aβ plaque-associated dystrophic axons results in lowered Aβ release and plaque deposition.
复制标题
DOI：
10.1002/alz.12144
复制
发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Brunden KR
中科院分区：
文献类型：
--
作者：
Yao Y;Nzou G;Alle T;Tsering W;Maimaiti S;Trojanowski JQ;Lee VM;Ballatore C;Brunden KR
阿尔茨海默病（AD）的标志性病理是含有a β的老年斑和由微管（MT）结合的tau蛋白形成的神经原纤维缠结。在AD中，Tau过度磷酸化并脱离MT，导致MT结构/功能缺陷。脑渗透mt稳定化合物可以使tau病理小鼠模型中的mt和轴突运输正常化，从而减少神经元损失和降低tau病理。在Aβ斑块附近的营养不良轴突中也观察到MT功能障碍，导致淀粉样蛋白前体蛋白（APP）和BACE1的积累，具有增强局部Aβ生成的潜力。我们研究了脑渗透mt稳定化合物CNDR-51657是否可能减少斑块相关的轴突营养不良和产生丰富的β斑块的5XFAD小鼠的Aβ释放。给1.5月龄的雄性和雌性5XFAD小鼠服用CNDR-51657 4周或7周，导致可溶性脑Aβ减少，同时APP和BACE1水平降低，导致不溶性Aβ沉积的形成减少。这些数据提示了一个恶性循环，即最初的a β斑块形成导致附近轴突的MT破坏，导致APP和BACE1的局部积累，从而促进额外的a β生成和斑块沉积。mt稳定化合物能够减弱这一循环，并减少tau蛋白与mt结合减少导致的缺陷，这表明这种类型的分子有望成为潜在的AD治疗药物。
The hallmark pathologies of the Alzheimer’s disease (AD) brain are Aβ-containing senile plaques and neurofibrillary tangles formed from the microtubule (MT)-binding tau protein. Tau becomes hyperphosphorylated and disengages from MTs in AD, with evidence of resulting MT structure/function defects. Brain-penetrant MT-stabilizing compounds can normalize MTs and axonal transport in mouse models with tau pathology, thereby reducing neuron loss and decreasing tau pathology. MT dysfunction is also observed in dystrophic axons adjacent to Aβ plaques, resulting in accumulation of amyloid precursor protein (APP) and BACE1 with the potential for enhanced localized Aβ generation. We have examined whether the brain-penetrant MT-stabilizing compound, CNDR-51657, might decrease plaque-associated axonal dystrophy and Aβ release in 5XFAD mice that develop an abundance of Aβ plaques. Administration of CNDR-51657 to 1.5-month old male and female 5XFAD mice for 4- or 7-weeks led to decreased soluble brain Aβ that coincided with reduced APP and BACE1 levels, resulting in decreased formation of insoluble Aβ deposits. These data suggest a vicious cycle whereby initial Aβ plaque formation causes MT disruption in nearby axons, resulting in the local accumulation of APP and BACE1 that facilitates additional Aβ generation and plaque deposition. The ability of a MT-stabilizing compound to attenuate this cycle, and also reduce deficits resulting from reduced tau binding to MTs, suggests that molecules of this type hold promise as potential AD therapeutics.
登录
查看更多内容
影响因子：
56.9
作者：
Hong, M;Zhukareva, V;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1097/00005072-199609000-00003
发表时间：
1996-09-01
影响因子：
3.2
作者：
Hempen, B;Brion, JP
通讯作者：
Brion, JP
影响因子：
6
作者：
Cash, AD;Aliev, G;Perry, G
通讯作者：
Perry, G
影响因子：
5.8
作者：
Cortes, Javier;Baselga, Jose
通讯作者：
Baselga, Jose
影响因子：
9.9
作者：
ARRIAGADA, PV;GROWDON, JH;HYMAN, BT
通讯作者：
HYMAN, BT