Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer's disease neuropathology.
Absence of amyloid β oligomers at the postsynapse and regulated synaptic Zn2+ in cognitively intact aged individuals with Alzheimer's disease neuropathology.
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DOI：
10.1186/1750-1326-7-23
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发表时间：
2012-05-28
影响因子：
15.1
通讯作者：
Taglialatela G
中科院分区：
文献类型：
--
作者：
Bjorklund NL;Reese LC;Sadagoparamanujam VM;Ghirardi V;Woltjer RL;Taglialatela G
阿尔茨海默病（Alzheimer Disease，AD）的早期认知功能障碍被认为是由β淀粉样蛋白（amyloid beta，Aβ）寡聚体靶向突触的功能障碍引起的。然而，尽管存在AD的神经病理学特征（Aβ斑块和神经元缠结），但一些个体逃避了认知下降。我们称这组非痴呆AD神经病理或NDAN。本研究阐明了NDAN病例中涉及的一种假定的耐药机制，这可能为AD的有效治疗提供了靶点。在这里，我们描述了定位的Aβ寡聚体在突触后在海马AD病例。然而，值得注意的是，我们还发现，虽然存在于可溶性组分中，但在NDAN病例中，海马后突触中不存在Aβ寡聚体。此外，磷酸化（活性）CREB的水平，突触可塑性的重要转录因子，是正常的NDAN个人，这表明他们的突触功能完整。锌离子的分析表明，水平增加的可溶性组分和突触囊泡在AD campi，突触囊泡锌离子转运蛋白，ZnT3的表达减少。相反，在NDAN个体中，可溶性组分中的Zn 2+水平显著低于AD，而突触囊泡中的Zn 2+水平与AD相似，但伴随着ZnT3的保留表达。综上所述，这些数据表明，与症状性AD受试者相比，尽管存在显著的AD神经病理学、Aβ寡聚体和突触囊泡Zn2+增加，但这些老年NDAN个体中的易感脑组织的特征是总Zn2+水平显著降低，并且Aβ寡聚体与突触后无关联，这共同可能促进完整认知功能的维持。
Early cognitive impairment in Alzheimer Disease (AD) is thought to result from the dysfunctional effect of amyloid beta (Aβ) oligomers targeting the synapses. Some individuals, however, escape cognitive decline despite the presence of the neuropathologic features of AD (Aβ plaques and neurofibrillary tangles). We term this group Non-Demented with AD Neuropathology or NDAN. The present study illustrates one putative resistance mechanism involved in NDAN cases which may suggest targets for the effective treatment of AD. Here we describe the localization of Aβ oligomers at the postsynapse in hippocampi from AD cases. Notably, however, we also found that while present in soluble fractions, Aβ oligomers are absent from hippocampal postsynapses in NDAN cases. In addition, levels of phosphorylated (active) CREB, a transcription factor important for synaptic plasticity, are normal in NDAN individuals, suggesting that their synapses are functionally intact. Analysis of Zn2+ showed that levels were increased in both soluble fractions and synaptic vesicles in AD hippocampi, paralleled by a decrease of expression of the synaptic vesicle Zn2+ transporter, ZnT3. Conversely, in NDAN individuals, levels of Zn2+ in soluble fractions were significantly lower than in AD, whereas in synaptic vesicles the levels of Zn2+ were similar to AD, but accompanied by preserved expression of the ZnT3. Taken together, these data illustrate that despite substantial AD neuropathology, Aβ oligomers, and increased synaptic vesicle Zn2+, susceptible brain tissue in these aged NDAN individuals features, as compared to symptomatic AD subjects, significantly lower total Zn2+ levels and no association of Aβ oligomers with the postsynapse, which collectively may promote the maintenance of intact cognitive function.
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影响因子：
3
作者：
Danscher, G;Jensen, KB;Ravid, R
通讯作者：
Ravid, R
影响因子：
3
作者：
Bjorklund, Nicole L.;Sadagoparamanujam, V. -M.;Taglialatela, Giulio
通讯作者：
Taglialatela, Giulio
DOI：
10.1523/jneurosci.1064-09.2009
发表时间：
2009-10-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Abdul HM;Sama MA;Furman JL;Mathis DM;Beckett TL;Weidner AM;Patel ES;Baig I;Murphy MP;LeVine H 3rd;Kraner SD;Norris CM
通讯作者：
Norris CM
影响因子：
4.2
作者：
Colvin, RA;Davis, N;Carter, PA
通讯作者：
Carter, PA
影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE