nELAV proteins alteration in Alzheimer's disease brain: a novel putative target for amyloid-beta reverberating on AbetaPP processing.
nELAV proteins alteration in Alzheimer's disease brain: a novel putative target for amyloid-beta reverberating on AbetaPP processing.
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DOI：
10.3233/jad-2009-0967
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Pasinetti GM
中科院分区：
文献类型：
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作者：
Amadio M;Pascale A;Wang J;Ho L;Quattrone A;Gandy S;Haroutunian V;Racchi M;Pasinetti GM
神经元ELAV（nELAV）蛋白是RNA结合蛋白，其在控制记忆形成中的基因表达中发挥生理作用，并且它们的改变可能导致与神经退行性病理如阿尔茨海默病（AD）相关的认知障碍。事实上，我们发现nELAV蛋白质的含量随着AD大脑中大脑皮层的临床痴呆进展而沿着显著降低，其中其与淀粉样蛋白-β（Aβ）的量呈负相关。为了检查Aβ对nELAV的直接影响，我们使用人SH-SY 5 Y细胞进行了体外实验，发现Aβ1-42特异性地决定了nELAV蛋白的减少。由于ADAM 10 mRNA具有nELAV靶向的预测序列，我们研究了Aβ是否可以通过nELAV蛋白引起影响淀粉样β蛋白前体（AβPP）加工的恶性循环。免疫沉淀实验表明，nELAV蛋白确实与ADAM 10 mRNA结合，并且这种结合被Aβ1-42暴露破坏，导致ADAM 10蛋白表达降低。在AD中也发现了ADAM 10蛋白的减少。这些数据首次表明nELAV参与AD病理学，并表明它们的改变可能影响AβPP加工相关基因。
Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer’s disease (AD). Indeed, we found that the content of nELAV proteins is significantly decreased along with clinical dementia progression in the hippocampi of AD brains, where it inversely correlates with the amount of amyloid-β (Aβ). To check the direct influence of Aβ on nELAV, we performed in vitro experiments using human SH-SY5Y cells, finding that Aβ1–42 specifically determines nELAV proteins reduction. Since ADAM10 mRNA has the predicted sequences targeted by nELAV, we investigated whether Aβ, through nELAV proteins, could originate a vicious circle affecting amyloid-β protein precursor (AβPP) processing. Immunoprecipitation experiments showed that indeed nELAV proteins bind to ADAM10 mRNA and that this binding is disrupted by Aβ1–42 exposure, resulting in a decreased ADAM10 protein expression. ADAM10 protein diminution was also found in AD hippocampi. These data show for the first time the involvement of nELAV in AD pathology and suggest that their alteration may affect genes implicated in AβPP processing.