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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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Chinese Journal of Alzheimer's Disease and Related Disorders >

2019 , Vol. 2 >Issue 2: 375 - 378

DOI: https://doi.org/10.3969/j.issn.2096-5516.2019.02.012

Study on pathologenesis of edogenous formaldehyde and inflammatory factors in Alzheimer's disease

  • ZHANG Shouzi ,
  • ZHANG Li ,
  • MA Li ,
  • WU Haiyan ,
  • CAO Meng
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  • Institute of Geriatrics of Beijing Geriatric Hospital

Received date: 2019-01-04

  Revised date: 2019-02-28

  Online published: 2019-06-25

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Abstract

Objective: To investigate the expression of uric endogenous formaldehyde and peripheral inflammatory factors in Alzheimer's disease (AD), as well as the associations between them. To explain the pathologenesis of uric formaldehyde in Alzheimer's disease, exploring if uric endogenous formaldehyde and peripheral inflammatory factors could be combined biomarkers for diagnosis of AD. Methods: Community-dwelling cognitive normal older adults (control group, n=54), Alzheimer's disease patients (AD group, n=44) were included. Uric formaldehyde and peripheral inflammatory (interleukin-2 IL-2, tumor necrosis factor-α, TNF-α) were measured in two groups using a double blind design. Results: Uric formaldehyde were elevated in AD group. Compared with the cognitive normal group (P< 0.05). There was no difference in IL-2 and TNF-α between the two groups. There was no significant difference in endogenous formaldehyde between the two groups according to whether hypertension existed or not. There weren't relationship between uric formaldehyde and peripheral inflammatory level (IL-2 and TNF-α). Conclusion: Our study suggests that the endogenous formaldehyde may be involved in the pathological process of Alzheimer's disease, and formaldehyde could be diagnosing biomarkers for AD combined peripheral inflammatory factors. Peripheral inflammation and hypertension may not be the origin initiating factors for increasing of formaldehyde in dementia individuals.

Key words： Alzheimer's disease; Endogenous formaldehyde; IL-2; TNF-α

Cite this article

ZHANG Shouzi , ZHANG Li , MA Li , WU Haiyan , CAO Meng . Study on pathologenesis of edogenous formaldehyde and inflammatory factors in Alzheimer's disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2019 , 2(2) : 375 -378 . DOI: 10.3969/j.issn.2096-5516.2019.02.012

阿尔茨海默病(Alzheimer's disease, AD)是一种以老年斑和神经纤维缠结为病理特点的神经变性病,淀粉前体样蛋白（Aβ）及磷酸化tau蛋白的神经毒性作用是其主要的发病机制[1]。脑脊液中的Aβ1-42和tau蛋白也作为生化标记物作为诊断的依据,但存在取样较为困难等原因在临床上没有得到广泛普及应用。有报道内源性甲醛在体外实验中能使tau蛋白过度磷酸化和蛋白错误折叠,推测过量的内源性甲醛（FA)和AD发病有密切关系[2-3]。内源性FA主要存在于脑脊液、血液及尿液中,如果AD患者检测尿液中含量升高,可以作为一种简单便捷的生化标记物用于临床诊断。
还有人通过分子生化研究发现阿尔茨海默病患者脑内的Aβ沉积区域及神经纤维缠结周围有慢性炎症反应,基因学研究也发现一些炎性因子如肿瘤坏死因子-α（TNF-α）、白细胞介素1α（IL-1α）、IL-1β、IL-6和α2巨球蛋白等与AD的发病过程有关[4]。本实验也拟研究内源性FA和炎症介质的关系,分析内源性FA的升高是否通过炎症反应所诱导,并研究内源性FA和高血压是否存在依从性关系。

1 资料与方法

1.1 研究对象

随机抽取社区内认知功能正常老年人54例为对照组[男/女：23/31,年龄（77.7±8.3）岁],入选标准：⑴MMSE> 26分,⑵无记忆障碍的主诉;⑶神经系统查体无异常。抽取北京老年医院精神心理科住院病房内诊断很可能是AD的患者44例作为AD组[男/女：18/26,年龄（75.2±5.3）岁],诊断标准：采用美国精神病学会精神障碍诊断和统计手册（DSM-Ⅳ）标准建立痴呆诊断。美国神经病学、语言障碍和卒中老年性痴呆和相关疾病学会（NINCDS/ADRDA）标准建立可能AD标准。入组被试者无感染、炎症、免疫病、肿瘤及营养不良;血液检测无C反应蛋白升高及白细胞计数异常。所有被试均签署了知情同意。

1.2 研究方法

留取被试者晨尿,并确保被试者在留标本前一周未进食油腻及辛辣食物。同一时间段用抗凝管留取被试者空腹血10 ml,离心机离心（3 000 r/min、10 min）留取上清液,尿液及血清均-80℃冰箱保存。
样本采集和检测采用双盲法,采用双抗体夹心法测定血清IL-2、TNF-α,试剂盒分别由北京邦定生物医学公司和深圳晶美生物有限公司提供。采用气相色谱方法测定尿液内源性FA含量[5-6],同时用临床检测系统UniCelR DxC 800 SynchronR（Beckman,美国）检测尿液中肌酐浓度,采用内源性FA和尿肌酐比值（FA/Cr）代表内源性FA含量,用以矫正尿液中内源性FA被严重稀释后数值过小[7],矫正后的数值能真实客观反映尿液中内源性FA浓度。

1.3 统计学方法

采用SPSS 15.0统计学软件进行统计学分析。对照组和AD组的性别、年龄及教育水平差异采用卡方检验,计量资料以均数±标准差来表示,两组之间比较采用t检验,P< 0.05代表差异有统计学意义。并采用Spearman相关模型做相关性分析。

2 结果

对照组和AD组在年龄、性别、受教育水平、有无高血压四个维度无显著性差异（见表1）。
表1 对照组和AD组的基本情况表
对照组(n=54) AD组 (n=32) 差异性
年龄 77.4±1.67 78.84±1.33 X2=0.125
性别（男） 40.74% 56.25% X2=0.313
受教育年限 6.7±1.2 7.5±2.7 X2=0.385
高血压 55.56% 43.75% X2=0.114
对照组和AD组的血浆IL-2、TNF-α浓度差异均无统计学意义（P=0.060,P=0.597）,阿尔茨海默病组尿液FA/Cr数值高于认知正常对照组,差异有统计学意义（P=0.007）（见表2）。
表2 对照组和AD组内源性FA及炎症介质对照表
对照组(n=54) AD组 (n=32) 差异性
TNF-α (μg/L) 307.27±12.48 328.88±37.16 P=0.597
IL-2 (μg/L) 972.33±30.35 1305.6±122.32 P=0.060
FA/Cr 4.40±0.31 5.52±0.54 **P=0.007
对照组依据是否有高血压分组,两亚组尿液FA/Cr数值对照无显著性差异（P=0.8）; AD组依据是否有高血压分组,两亚组尿液FA/Cr数值对照均无显著性差异（P=0.28）（见表3）。
表3 对照组和AD组按高血压分组的内源性AD对照表
FA/Cr 正常血压组 高血压组 差异性
对照组 4.99±0.42 3.91±0.44 P=0.08
AD组 6.04±0.77 4.84±0.71 P=0.28
AD组中血浆IL-2、TNF-α浓度显示有密切相关性（R2=0.6912）（图1）; AD组中血浆IL-2浓度和尿液内源性甲醛（FA）浓度无相关性（R2=0.088）（图2）; AD组中血浆TNF-α浓度和尿液内源性甲醛（FA）浓度亦无相关性R2=0.0232（图3）。
图1 TNF-α和IL-2相关性指示图（横坐标数值为TNF-α数值,纵坐标为IL-2数值）
图2 内源性FA和IL-2相关性指示图（横坐标数值为FA数值,纵坐标为IL-2数值）
图3 内源性FA和TNF-α相关性指示图（横坐标数值为FA数值,纵坐标为TNF-α数值）

3 讨论

阿尔茨海默病（AD）的发病机制包含了淀粉前体样蛋白的沉积,如Aβ在神经元细胞外的沉积及tau 蛋白的磷酸化,且脑脊液中A ß1-42及磷酸化tau含量水平已经成为诊断AD的生物标记物。其病理特征为老年斑及神经纤维缠结形成,在这些特异性病变内部及周边也存在着慢性炎症反应,如炎症因子过度表达、补体激活、星型细胞增多及胶质细胞增多等,老年斑的形成和炎症因子前体物（TNF-α, IL-6, IL-1α, IL-1β）以及免疫抑制标记物（IL-4, IL-10, IL-2, IL-3,血管内皮生长因子）密切相关[8]。有研究证实这些炎症因子的升高和tau蛋白呈负相关,由此推断炎症因子可能在AD的发病过程中起到神经保护的作用[9]。本实验检测了尿液内源性甲醛及血液中TNF-α, IL-2,发现TNF-α、IL-2在AD组中轻度升高,但没有统计学意义。
内源性甲醛是人体正常生理代谢产物,正常情况下有一个恒定的浓度,动物及体外实验证明过量内源性甲醛可以促进Aβ沉积及神经纤维缠结形成[10-11],体外实验更证实其可以导致tau蛋白的异常折叠作用[3],很低的浓度（0.01-0.1%)可以导致淀粉样蛋白样tau沉积,从而造成海马细胞的凋亡。从而推测内源性甲醛是导致AD发病的一个重要机制[12]。
本实验检测了尿液内源性甲醛在AD组中较对照组明显升高,这也和之前中国科学院生物物理所做的研究相符合,赫荣乔教授团队也曾经发现在老年性痴呆患者中,尿液内源性甲醛含量同简易智能量表（MMSE)呈负相关。他们也推测内源性甲醛是造成散发性AD发病的重要影响因素[13]。有人在动物实验中发现年龄增长相关的海马中过量内源性甲醛聚集可以导致记忆力下降,而DNA甲基化是记忆形成的重要过程,无论是在高龄大鼠AD模型还是在AD患者的脑切片中,DNA甲基化功能都有所下降[14,15],有人推测内源性甲醛是通过影响DNA甲基化功能促成AD发病的[16]。
我们的实验也发现不论在对照组还是ADAD组中,内源性甲醛含量和是否合并有高血压无关,也和血液中检测的TNF-α及IL-2浓度无相关性,说明AD患者内源性甲醛的升高的机制可能不是炎症因子启动的,其升高也不受高血压病的诱导,尿液内源性甲醛含量可以作为AD早期诊断的潜在辅助生物标记物,而一些炎症因子虽然可能参与了AD的发病过程,但在血液中含量变化甚微,临床应用价值不大。
利益关系陈述：我们在此声明本课题在研究过程中或得到的结果未受到任何机构或厂商的影响。

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