Aboud Orwa, Parcon Paul A, DeWall K Mark, Liu Ling, Mrak Robert E, Griffin W Sue T
Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA.
Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA ; Department of Biology, Brigham Young University Idaho, Rexburg, ID, USA.
Front Cell Neurosci. 2015 Mar 25;9:103. doi: 10.3389/fncel.2015.00103. eCollection 2015.
Reports from neural cell cultures and experimental animal studies provide evidence of age- and disease-related changes in retrograde transport of spent or misfolded proteins destined for degradation or recycling. However, few studies address these issues in human brain from those who either age without dementia and overt neuropathology, or succumb to Alzheimer's; especially as such propensity may be influenced by APOE genotype. We studied the expression and distribution of the dynein subunit dynactin-P50, the β amyloid precursor protein (βAPP), and hyperphosphorylated tau (P-tau) in tissues and tissue sections of brains from non-demented, neuropathology-free patients and from Alzheimer patients, with either APOE ε3,3 or APOE ε4,4. We found that advanced age in patients without dementia or neuropathological change was associated with coordinated increases in dynactin-P50 and βAPP in neurons in pyramidal layers of the hippocampus. In contrast, in Alzheimer's, βAPP and dynactin were significantly reduced. Furthermore, the dynactin-P50 and βAPP that was present was located primarily in dystrophic neurites in Aβ plaques. Tissues from Alzheimer patients with APOE ε3,3 had less P-tau, more βAPP, dynactin-P50, and synaptophysin than did tissues from Alzheimer patients carrying APOE ε4,4. It is logical to conclude, then, that as neurons age successfully, there is coordination between retrograde delivery and maintenance and repair, as well as between retrograde delivery and degradation and/or recycling of spent proteins. The buildup of proteins slated for repair, synaptic viability, transport, and re-cycling in neuron soma and dystrophic neurites suggest a loss of this coordination in Alzheimer neurons. Inheritance of APOE ε3,3 rather than APOE ε4,4, is associated with neuronal resilience, suggestive of better repair capabilities, more synapses, more efficient transport, and less hyperphosphorylation of tau. We conclude that even in disease the ε3 allele is neuroprotective.
神经细胞培养和实验动物研究的报告提供了证据，表明在用于降解或再循环的消耗或错误折叠蛋白质的逆行运输中存在与年龄和疾病相关的变化。然而，很少有研究在未患痴呆症且无明显神经病理学的老年人或死于阿尔茨海默病的人的大脑中探讨这些问题；特别是因为这种倾向可能受载脂蛋白E（APOE）基因型的影响。我们研究了动力蛋白亚基动力肌动蛋白P50、β淀粉样前体蛋白（βAPP）和过度磷酸化tau蛋白（P-tau）在无痴呆、无神经病理学患者以及阿尔茨海默病患者（APOE ε3,3或APOE ε4,4）的脑组织和组织切片中的表达和分布。我们发现，无痴呆或神经病理学变化患者的高龄与海马锥体细胞层神经元中动力肌动蛋白P50和βAPP的协同增加有关。相比之下，在阿尔茨海默病中，βAPP和动力肌动蛋白显著减少。此外，存在的动力肌动蛋白P50和βAPP主要位于Aβ斑块中的营养不良性神经突中。与携带APOE ε4,4的阿尔茨海默病患者的组织相比，携带APOE ε3,3的阿尔茨海默病患者的组织中P-tau更少，βAPP、动力肌动蛋白P50和突触素更多。因此，可以合理地得出结论，随着神经元成功老化，逆行运输与维持和修复之间以及逆行运输与消耗蛋白质的降解和/或再循环之间存在协调。在神经元胞体和营养不良性神经突中，用于修复、突触活力、运输和再循环的蛋白质积累表明阿尔茨海默病神经元中这种协调的丧失。APOE ε3,3而非APOE ε4,4的遗传与神经元弹性相关，提示更好的修复能力、更多的突触、更有效的运输以及更少的tau蛋白过度磷酸化。我们得出结论，即使在疾病中，ε3等位基因也具有神经保护作用。
