【摘要】：衰老相關(guān)的認(rèn)知損傷,如阿爾茨海默病(AD),是一種緩慢、漸進(jìn)、不可逆的神經(jīng)退行性疾病.內(nèi)源(尿)甲醛濃度與AD病人的認(rèn)知損害程度呈正相關(guān).但是,在以前研究中所采用的甲醛濃度,通常高于AD患者和老年人的病理和生理濃度.因此,研究長(zhǎng)時(shí)程低濃度(病理濃度)甲醛對(duì)神經(jīng)類細(xì)胞的影響,對(duì)于揭示甲醛在AD發(fā)生發(fā)展過(guò)程的作用是非常必要的.本文參照AD患者尿甲醛濃度,采用每隔24 h連續(xù)傳代接種加甲醛(10μmol/L)的方式,模擬AD病人尿甲醛濃度,觀察長(zhǎng)時(shí)程甲醛的累積對(duì)小鼠神經(jīng)母瘤細(xì)胞(N2a)和原代海馬神經(jīng)元的影響.通過(guò)高效液相色譜、細(xì)胞活力和乳酸脫氫酶釋放檢測(cè)顯示,隨著孵育時(shí)間的延長(zhǎng),培養(yǎng)基內(nèi)甲醛濃度積累升高,N2a細(xì)胞生長(zhǎng)受到抑制,在甲醛孵育的后期,細(xì)胞死亡顯著增加.全息成像顯示,長(zhǎng)時(shí)程病理濃度甲醛的積累,使細(xì)胞厚度增加、面積減小、神經(jīng)突受損、顯著削弱細(xì)胞的黏附能力.同樣條件下,小鼠原代海馬神經(jīng)元的一級(jí)神經(jīng)突的數(shù)目顯著降低,表明病理濃度甲醛的積累能夠削弱神經(jīng)元之間的連接.免疫印跡和免疫熒光染色顯示,甲醛的累積可以使N2a細(xì)胞內(nèi)Tau蛋白的181位蘇氨酸(T181)和396位絲氨酸(S396)磷酸化水平顯著上升,可能是甲醛累積導(dǎo)致的神經(jīng)突減少和形態(tài)改變的因素之一.以上結(jié)果證明,病理濃度甲醛在細(xì)胞生存環(huán)境中的累積,可以導(dǎo)致神經(jīng)細(xì)胞損傷,尤其是神經(jīng)突的異常改變.本文為探索甲醛代謝失調(diào)與老年認(rèn)知損害之間關(guān)系和機(jī)制提供了新的啟示.
[Abstract]:Aging-related cognitive impairment, such as Alzheimer's disease (AD), is a slow, progressive, irreversible neurodegenerative disease. There was a positive correlation between the concentration of endogenous formaldehyde and the degree of cognitive impairment in patients with AD. However, the formaldehyde concentration used in previous studies is usually higher than the pathological and physiological concentrations in AD patients and the elderly. Therefore, it is necessary to study the effect of long-term low concentration (pathological concentration) formaldehyde on neural cells in order to reveal the role of formaldehyde in the occurrence and development of AD. According to the urine formaldehyde concentration of AD patients, the urine formaldehyde concentration of AD patients was simulated by continuous passage vaccination with formaldehyde (10 渭 mol / L) every 24 hours. To observe the effect of long-term formaldehyde accumulation on mouse neuroblastoma cells (N2A) and primary hippocampal neurons. The results of high performance liquid chromatography (HPLC), cell activity and lactic dehydrogenase release showed that with the prolongation of incubation time, the accumulation of formaldehyde in the culture medium increased, the growth of N2A cells was inhibited, and the cell death increased significantly at the later stage of formaldehyde incubation. Holographic imaging showed that the accumulation of formaldehyde in long-term pathological concentration increased the thickness of cells, decreased the area, damaged the nerve process, and significantly weakened the adhesion ability of cells. Under the same conditions, the number of primary hippocampal neurons in mice decreased significantly, indicating that the accumulation of formaldehyde in pathological concentration could weaken the connection between neurons. Western imprinting and immunofluorescence staining showed that the accumulation of formaldehyde could significantly increase the phosphorylation of Tau protein T181 and S396 in N2A cells. It may be one of the factors leading to the decrease of neuroprocesses and morphological changes caused by formaldehyde accumulation. These results show that the accumulation of formaldehyde in the cell survival environment can lead to nerve cell injury, especially the abnormal changes of nerve processes. This paper provides a new enlightenment for exploring the relationship and mechanism between formaldehyde metabolism disorder and cognitive impairment in the elderly.
【作者單位】： 重慶醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院生物化學(xué)與分子生物學(xué)教研室;中國(guó)科學(xué)院生物物理研究所腦與認(rèn)知國(guó)家重點(diǎn)實(shí)驗(yàn)室;
【基金】：supported by grants from National Basic Research Program of China(2012CB911004) The National Natural Science Foundation of China(31270868,31200601)~~
【分類號(hào)】：R749.16

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