School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.
Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
J Alzheimers Dis. 2018;64(1):223-237. doi: 10.3233/JAD-180032.
Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.
淀粉样蛋白-β 前体（AβPP）的失调在阿尔茨海默病（AD）的神经退行性级联反应中起着关键作用。重要的是，5,10-亚甲基四氢叶酸还原酶（MTHFR）基因中的常见功能多态性是迟发性 AD 发病的危险因素。MTHFR 活性降低与叶酸和同型半胱氨酸代谢的改变有关。在这里，我们首先表明，在年轻的 MTHFR 敲除小鼠中，轻度和重度 MTHFR 缺乏症明显增加皮质和海马 AβPP 在调节 Thr668 位点的磷酸化。然而，海马体特别容易受到衰老和轻度 MTHFR 缺乏的影响。值得注意的是，在年轻小鼠中严重 MTHFR 缺乏的影响通过在老年小鼠中延长叶酸缺乏饮食来重现，这导致胱硫醚由于同型半胱氨酸甲基化受损而在大脑区域积累。严重的遗传或饮食诱导的叶酸循环损伤介导的 AβPP 在 Thr668 处的递增磷酸化与去甲基化蛋白磷酸酶 2A（PP2A）的积累增强以及糖原合酶激酶-3β（GSK-3β）的激活相关。最后，我们表明，叶酸代谢的严重紊乱也可以以大脑区域特异性的方式影响 AβPP 的表达水平。总之，我们的研究结果确定了 MTHFR 基因缺陷、GSK-3β 激活、PP2A 去甲基化和 AβPP 在 Thr668 处磷酸化增强之间的新联系，已知这会严重影响神经元 AβPP 功能和病理性淀粉样蛋白加工。AβPP 的失调提供了一种新的机制，通过该机制，常见的人类 MTHFR 多态性可能与饮食叶酸缺乏相互作用，改变神经元内稳态并增加散发 AD 的风险。
