Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport.
Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport.
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DOI：
10.1186/s13195-021-00796-6
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发表时间：
2021-03-10
期刊：
影响因子：
--
通讯作者：
Mobley WC
中科院分区：
文献类型：
--
作者：
Chen XQ;Das U;Park G;Mobley WC
轴突运输受损可能参与神经退行性疾病的发病，包括阿尔茨海默病(AD)和唐氏综合征(DS)。轴突运输是一个复杂的过程，在这个过程中，特定的运动蛋白将货物运送到神经元细胞体及其突起。不一致的报道指出，在AD中经典的顺行运动蛋白家族成员5(KIF5)和初级神经元KIF调节因子轻链1(KLC1)的水平发生了变化，这增加了AD顺行转运受到损害的可能性。为了解决不一致的问题，并确定AD和老年DS痴呆患者(AD in DS；AD-DS)的共同病理是否延伸到KIF5和KLC1的变化，我们测量了所有三个KIF5家族成员和KLC1在AD和AD-DS额叶皮质以及AD颞叶皮质和小脑中的水平，并在较短的尸检间隔内采集样本。为了支持未来的研究，以探索检测到的任何变化的细胞生物学基础，我们还检测了DP(16)1Yey/+(Dp16)DS小鼠模型和J20 AD小鼠模型中年轻和老年成年小鼠脑中这些蛋白质的水平。当归一化为β肌动蛋白或3-磷酸甘油醛脱氢酶时，在AD或AD-DS样本中，Kif5家族成员与对照组相比没有变化。然而，有趣的是，来自对照大脑以及AD和AD-DS的样本显示，KIF5家族成员的水平之间存在强烈的正相关，这表明存在正的共同调控表达。重要的是，虽然早期的报告指出淀粉样前体蛋白(APP)水平和KIF5A水平之间存在负相关，但我们发现AD-DS的情况正好相反；考虑到APP基因的三倍增长，APP蛋白水平增加，这一点尤其显著。AD和对照样本显示FL-HAPP和KIF5成员之间存在正相关，但它们的一致性较差。与KIF5的发现相反，在AD和AD-DS大脑的额叶皮质中，KLC1的水平都被下调；有趣的是，这种变化在AD的颞叶皮质或小脑中看不到。由于死后间隔对KLc1水平有负面影响，但Kif5成员没有，我们分析了死后间隔非常短的样本子集(≤6 h)，该PMI与AD或AD-DS样本中的KLc1水平没有显著相关性；我们证实，与对照组相比，AD和AD-DS脑中KLc1的水平存在统计学上的显著降低。将Dp16与其整倍体对照进行比较的研究概括了人类研究，证明KIF5水平没有变化，KIF5家族成员之间存在正相关。J20小鼠也表现出正常的KIF5水平。然而，与AD和AD-DS额叶皮质不同，Dp16或J20小鼠的大脑中KLC1水平并没有降低。这些数据表明AD和AD-DS患者的KLC1显著降低。在这样做的过程中，他们增加了在这些条件下KLC1介导的轴突运输受损的可能性，这一假设现在可以在KLC1表达减少的模型系统中继续进行。网上版载有补充材料，可在10.1186/s13195-021-00796-6查阅。
Impaired axonal transport may contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) and Down syndrome (DS). Axonal transport is a complex process in which specific motor proteins move cargoes to and from neuronal cell bodies and their processes. Inconsistent reports point to the changes in AD in the levels of the classical anterograde motor protein kinesin family member 5 (KIF5) and the primary neuronal KIF regulator kinesin light chain 1 (KLC1), raising the possibility that anterograde transport is compromised in AD. To address inconsistencies and determine if the shared pathologies in AD and elderly DS subjects with dementia (AD in DS; AD-DS) extend to the changes in KIF5 and KLC1, we measured the levels of all the three KIF5 family members and KLC1 in the AD and AD-DS frontal cortex and AD temporal cortex and cerebellum in samples taken with a short postmortem interval. To support future studies to explore the cell biological basis for any changes detected, we also examined the levels of these proteins in the brains of young and aged adult mice in the Dp (16)1Yey/+ (Dp16) mouse model of DS and J20 mouse model of AD. There were no changes in comparison with controls in KIF5 family members in either the AD or AD-DS samples when normalized to either β-actin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Interestingly, however, samples from control brains as well as from AD and AD-DS demonstrated strong positive correlations between the levels of KIF5 family members, suggesting positive co-regulated expression. Importantly, while earlier reports pointed to a negative correlation between the levels of the amyloid precursor protein (APP) and KIF5A levels, we found the opposite to be true in AD-DS; this was especially striking given triplication of the APP gene, with increased APP protein levels. AD and control samples showed positive correlations between fl-hAPP and KIF5 members, but they were less consistent. In contrast to the findings for KIF5, the levels of KLC1 were downregulated in the frontal cortex of both AD and AD-DS brains; interestingly, this change was not seen in the AD temporal cortex or cerebellum. As postmortem interval has a negative effect on the levels of KLC1, but not KIF5 members, we analyzed a subset of samples with a very short postmortem interval (PMI) (≤ 6 h), a PMI that was not significantly correlated with the levels of KLC1 in either AD or AD-DS samples; we confirmed the presence of a statistically significant reduction of KLC1 in AD and AD-DS brains as compared with control brains. Studies comparing Dp16 to its euploid control recapitulated human studies in demonstrating no change in KIF5 levels and a positive correlation between the levels of KIF5 family members. J20 mice also showed normal KIF5 levels. However, unlike the AD and AD-DS frontal cortex, KLC1 levels were not reduced in the brains of Dp16 or J20 mice. These data point to significant reductions in KLC1 in AD and AD-DS. In so doing, they raise the possibility of compromised KLC1-mediated axonal transport in these conditions, a posit that can now be pursued in model systems in which KLC1 expression is reduced. The online version contains supplementary material available at 10.1186/s13195-021-00796-6.
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影响因子：
7.4
作者：
Chen XQ;Sawa M;Mobley WC
通讯作者：
Mobley WC
靶向唐氏综合症的APP水平增加：POSIPHEN介导的APP及其产品的降低及其产品在TS65DN小鼠模型中反向内体表型。
DOI：
10.1002/alz.12185
发表时间：
2021-03
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Chen XQ;Salehi A;Pearn ML;Overk C;Nguyen PD;Kleschevnikov AM;Maccecchini M;Mobley WC
通讯作者：
Mobley WC
影响因子：
5.3
作者：
Didonna, Alessandro;Opal, Puneet
通讯作者：
Opal, Puneet
影响因子：
25
作者：
Bosco, Daryl A.;Morfini, Gerardo;Karabacak, N. Murat;Song, Yuyu;Gros-Louis, Francois;Pasinelli, Piera;Goolsby, Holly;Fontaine, Benjamin A.;Lemay, Nathan;McKenna-Yasek, Diane;Frosch, Matthew P.;Agar, Jeffrey N.;Julien, Jean-Pierre;Brady, Scott T.;Brown, Robert H., Jr.
通讯作者：
Brown, Robert H., Jr.
影响因子：
11.8
作者：
Dictenberg, Jason B.;Swanger, Sharon A.;Bassell, Gary J.
通讯作者：
Bassell, Gary J.