Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is associated with increased risk for autism spectrum disorder (ASD), anxiety, ADHD, and epilepsy. While our understanding of FXS pathophysiology has improved, a lack of validated blood-based biomarkers of disease continues to impede bench-to-bedside efforts. To meet this demand, there is a growing effort to discover a reliable biomarker to inform treatment discovery and evaluate treatment target engagement. Such a marker, amyloid-beta precursor protein (APP), has shown potential dysregulation in the absence of fragile X mental retardation protein (FMRP) and may therefore be associated with FXS pathophysiology. While APP is best understood in the context of Alzheimer disease, there is a growing body of evidence suggesting the molecule and its derivatives play a broader role in regulating neuronal hyperexcitability, a well-characterized phenotype in FXS. To evaluate the viability of APP as a peripheral biological marker in FXS, we conducted an exploratory ELISA-based evaluation of plasma APP-related species involving 27 persons with FXS (mean age: 22.0 ± 11.5) and 25 age- and sex-matched persons with neurotypical development (mean age: 21.1 ± 10.7). Peripheral levels of both Aβ(1-40) and Aβ(1-42) were increased, while sAPPα was significantly decreased in persons with FXS as compared to control participants. These results suggest that dysregulated APP processing, with potential preferential β-secretase processing, may be a readily accessible marker of FXS pathophysiology.

中文翻译：

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脆性X综合征的外周淀粉样前体蛋白衍生物表达。

脆性X综合征（FXS）是最常见的智力障碍遗传形式，与自闭症谱系障碍（ASD），焦虑症，多动症和癫痫症的风险增加相关。尽管我们对FXS病理生理学的了解有所提高，但缺乏经过验证的以血液为基础的疾病生物标记物仍在阻碍从实验室到病床的工作。为了满足这种需求，人们正在努力寻找一种可靠的生物标记物，以告知治疗发现并评估治疗靶标的参与度。这种标记物淀粉样β前体蛋白（APP）在缺乏脆弱的X智力障碍蛋白（FMRP）的情况下显示出潜在的调节异常，因此可能与FXS​​病理生理有关。虽然APP在阿尔茨海默氏病的背景下得到了最好的理解，越来越多的证据表明，该分子及其衍生物在调节神经元过度兴奋性（FXS中特征明确的表型）中起着更广泛的作用。为了评估作为FXS外围生物标记的APP的可行性，我们进行了基于ELISA的血浆APP相关物种的探索性评估，涉及27个FXS（平均年龄：22.0±11.5）和25个年龄和性别匹配的人具有典型神经发育（平均年龄：21.1±10.7）。与对照组相比，FXS患者的Aβ（1-40）和Aβ（1-42）的外周水平均升高，而sAPPα显着降低。这些结果表明，APP加工失调以及潜在的优先β分泌酶加工，可能是FXS病理生理学的一个容易获得的标志。