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    內源性甲醛與人類記憶形成與衰退的關系

    來源:原創論文網 添加時間:2020-04-15

      摘    要: 甲醛是地球上進化早期階段最早出現的同時含有C、H、O元素的最簡單有機小分子之一,被發現存在于每一個真核細胞中,并參與“一碳代謝”。近期研究表明,內源性甲醛可能作為信號分子參與記憶的形成。電刺激或學習訓練后,大鼠腦內甲醛含量瞬時升高,激活N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受體,促進長時程增強(long-termpotentiation,LTP)或空間記憶的形成。相反,降低腦內甲醛含量后,NMDA受體不能被激活,伴隨LTP和短時記憶不能形成。在正常老年大鼠和癡呆小鼠中,腦內甲醛濃度異常升高,NMDA受體活性受到抑制,空間記憶受損。因此,維持體內生理水平的甲醛濃度對于記憶的形成與儲存尤為必要。本文對內源性甲醛在學習和記憶中的生理與病理生理學功能進行了綜述。

      關鍵詞: 內源甲醛; 癡呆; NMDA受體; 長時程增強; 空間記憶;

      Abstract: Formaldehyde is one of the simplest organic small molecules containing C, H and O elements in the early stage of earth's evolution; however, it has been found to be existed in every eukaryotic cell and participate in “one carbon metabolism” Recent studies have shown that formaldehyde may act as a signal molecule to regulate memory formation. After electrical stimulation or learning activity, the contents of formaldehyde in rat brains were increased instantly, and N-methyl-D-aspartate(NMDA)-receptor was activated to promote the formation of long-term potentiation(LTP) or spatial memory. On the contrary, after reducing the contents of formaldehyde in the brains, NMDA receptor could not be activated, which was accompanied by the deficits in both LTP and memory. Moreover, in the brains of normal aged rats and dementia mice, the concentrations of formaldehyde were abnormally increased, which directly inhibited NMDA receptor activity and impaired spatial memory. This article reviewed the physiological and pathophysiological functions of endogenous formaldehyde in learning and memory.

      Keyword: endogenous formaldehyde; Alzheimer's disease; N-methyl-D-aspartate receptor; long-term potentiation; spatial memory;

      甲醛(MW=30)是地球進化早期最先出現的、最簡單的同時含有C、H、O元素的有機小分子[1]。其他的小分子如NO(MW=30)、CO(MW=28)、H2S(MW=34)等伴隨生物的進化進入生命體后,能在腦部合成,并作為氣態信號分子參與學習和記憶[2]。目前研究表明,內源性甲醛存在于一切生物的細胞質、細胞核、亞細胞器中[3]。Heck等采用氣相-質譜色譜方法測得動物和人的血液中甲醛濃度一般為0.08 mmol/L,腦組織內為0.2~0.4 mmol/L[4]。近年來研究顯示,內源性甲醛參與記憶的形成,并與人類許多重大疾病密切相關[5]。伴隨年齡增加而在海馬中蓄積的甲醛可能是誘發記憶衰退的關鍵因素之一[6]。

      1 、外源甲醛暴露誘發記憶衰退

      氣態甲醛誘發記憶衰退現象,最早的報道出現在20世紀80年代的美國。室內裝潢甲醛污染、甲醛工業污染等,造成工作環境中人員記憶衰退,引起科學家的極大關注[7,8]。動物研究顯示,甲醛暴露可誘發大鼠記憶下降[9]。腹腔注射甲醛可致大鼠海馬和皮層神經元死亡[10,11]。氣態甲醛也降低小鼠空間記憶[12,13],顯著抑制記憶相關的海馬神經遞質的合成[14,15]。這說明甲醛損壞海馬是外源甲醛暴露誘發空間記憶缺失的主要原因。
     

    內源性甲醛與人類記憶形成與衰退的關系
     

      2 、內源性甲醛蓄積誘發記憶衰退

      1989年,Khokhlov等發現多發性硬化患者的血液和腦脊液中甲醛濃度異常上升,而甘氨酸能降低甲醛濃度,對病情有緩解作用[16]。雖然多發性硬化患者常常伴有記憶衰退,但該研究沒有對甲醛與記憶的關系進行探討。

      2.1、 記憶退化與甲醛蓄積的臨床研究證據

      Conaway等檢測了421例不同年齡健康受試者血液甲醛濃度,發現血液甲醛濃度基本穩定在0.08 mmol/L,這是因為血液中存在較強的甲醛緩沖體系,但隨著年齡的增加,血液甲醛濃度呈現逐漸增加的趨勢[17]。Tong等研究顯示,236例不同年齡健康受試者尿液中甲醛濃度基本穩定在0.06 mmol/L,但是隨著年齡的增長,呈現顯著升高[18]。Tong等檢測了141例不同程度癡呆患者的尿液,發現尿液甲醛濃度隨癡呆程度增加而顯著增高[6]。上述研究提示,年齡增長和神經退行性疾病可能導致內源性甲醛含量的升高。

      2.2、 記憶退化與甲醛蓄積的基礎研究證據

      衰老是唯一被確定了的誘發癡呆因素。加速老化模型SAMP8小鼠、鏈脲霉素STZ-誘發糖尿病模型大鼠造模成功后一個月記憶下降時,海馬中甲醛也明顯增加[19,20]。在APP單轉基因癡呆小鼠模型中,6月齡記憶明顯下降時,全腦水平甲醛濃度上升最明顯[6]。在APP/PS1雙轉基因癡呆小鼠模型中,3月齡記憶明顯下降時,全腦甲醛濃度顯著上升[6]。Tong等研究提出了關鍵證據:根據癡呆小鼠全腦中甲醛水平,用甲醛(0.5 mmol/L,i.p.)處理正常小鼠,Morris水迷宮試驗結果顯示小鼠記憶喪失[6],這提示海馬中蓄積的甲醛可能是記憶衰退的關鍵原因。

      3、 體內甲醛蓄積的多重原因

      正常腦內的甲醛生理濃度約為0.3 mmol/L。但隨著老年化或癡呆發生,腦部蓄積的甲醛逐步達到病理濃度(約0.5 mmol/L)[6],超過體內甲醛降解酶的降解能力,誘發神經元死亡、記憶下降。甲醛的生成和降解酶是調節腦內甲醛平衡的主要途徑(圖1)[5]。

      圖1.內源性甲醛代謝途徑
    圖1.內源性甲醛代謝途徑

      Fig.1.The multiple pathways of endogenous formaldehyde metabolism.Red arrows:formaldehyde generation pathways;blue arrows:formaldehyde degradation pathways.ADH1,alcohol dehydrogenase 1;ADH3,alcohol dehydrogenase 3;ALDH2,aldehyde dehydrogenase 2;LSD1,lysine special demethylase 1;SSAO,Semicarbazide-sensitive amine oxidase;SARDH,sarcosine dehydrogenase;SA,sarcosine;TET1,tet methylcytosine dioxygenase 1;CAT,catalase;MMA,monomethylamine;FA,formaldehyde;MeOH,methanol;ER,endoplasmic reticulum;LYS,lysosome;MIT,mitochondria.

      3.1、 甲醛降解酶

      甲醛降解主要由依賴谷胱甘肽(glutathione,GSH)的甲醛脫氫酶(formaldehyde dehydrogenase,FDH,又稱乙醇脫氫酶3,ADH3)、乙醇脫氫酶1(alcohol dehydrogenases 1,ADH1)、不依賴GSH的醛類脫氫酶2(aldehyde dehydrogenases II,ALDH2)進行;其次,S-甲基GSH脫氫酶、醛酮變位酶、過氧化氫酶(catalase,CAT)也能降解甲醛。FDH在腦白質中有強表達,灰質中有中度表達,能抵抗衰老誘發的神經退化[21],但它的活力在不同組織中有12~30倍的差別,在肝、腎、胃、腸中活力最高,在腦、心、肺、睪丸中活力最低[22]。ALDH2降解甲醛的Km值為0.5mmol/L,比FDH(Km=0.3 mmol/L)的降解能力強[23]。在生理條件下,甲醛主要由依賴GSH的ADH3降解,當體內甲醛濃度過高時,不依賴GSH的ALDH2發揮更重要的降解作用[24]。Ohta等研究顯示,當ALDH2活力低下時,記憶明顯下降[25]。Murta等研究顯示,當GSH耗竭時,CAT成為Fischer大鼠肺部降解甲醛的主要酶[26]。Tong等研究顯示,抑制FDH和ALDH2活性可導致大鼠海馬甲醛急劇蓄積,引發記憶下降[18]。

      3.2、 甲醛生成酶

      甲醛主要由下列酶促生成:肌氨酸脫氫酶(sarcosine dehydrogenase,SARDH)[27]、TET甲基胞嘧啶雙加氧酶1(tet methylcytosine dioxygenase 1,TET1)[28,29]、賴氨酸特異性脫甲基化酶1(lysine special demethylase 1,LSD1)[30,31]、內質網脫甲基化酶、氨基脲敏感的胺類氧化酶、脂類氧化酶、線粒體細胞色素P450酶等[5]。其中,DNA脫甲基化酶和基因的激活、轉錄、翻譯有關,它脫甲基時產生甲醛[28,32,33,34]。研究顯示,DNA轉甲基化酶的抑制劑5-Aza-2’-deoxycytidine能促進DNA脫甲基,產生甲醛蓄積[35]。

      3.3、 食物、藥物、環境污染因素

      研究顯示,香菇、黃瓜和牡蠣等食物能導致體內甲醛上升并超過0.3 mmol/L,一些藥物、環境污染物(如甲醛污染、離子輻射、汞污染、百草枯、甲胺)及抗癌藥物(如丁酸、AN-7、mitoxantrone)等也可以通過線粒體細胞色素P450酶轉化產生甲醛[3]。

      3.4、 老化、老年性疾病因素

      植物、動物、人的老化都增加體內甲醛的蓄積[6,36]。甲醛在多種疾病患者體內蓄積顯著,多項研究顯示,白血病患者血液[37]、前列腺癌、膀胱癌患者的尿液[38]、肺癌患者的呼出氣體[39]、肺癌細胞誘發的骨癌痛模型的骨髓、脊髓[40]、癡呆患者的尿液、海馬和癡呆模型的海馬[6]中的甲醛濃度升高。

      3.5 、基因因素

      在生理條件下,甲醛主要由依賴GSH的ADH3降解。ADH3基因多態現象很常見,與癡呆有一定聯系[41,42]。ADH3基因的敲除導致小鼠對甲醛的耐受性明顯降低[43]和果蠅視覺記憶缺失[44]。當體內甲醛濃度過高時,不依賴GSH的ALDH2發揮更重要的降解作用[24]。研究顯示,ALDH2多態現象與癡呆密切相關,日本和中國的病例對照研究顯示,ALDH2*2等位基因攜帶者患晚發性癡呆的概率較非攜帶者顯著增高,并與載脂蛋白E等位基因4(APOEε4)協同作用[45,46]。ALDH2基因的突變導致人肝臟降解甲醛能力下降10%[47]。ALDH2基因敲除的小鼠表現出記憶缺失[25,48,49]。當GSH耗竭時,CAT成為降解甲醛的主要酶。CAT基因在癡呆患者人群有多態現象,CAT基因在其啟動子區域(rs1001179)的-262位具有C/T多態性,T啟動子變體可以增強該基因的轉錄活性和酶活力,特別是TT純合子和CT雜合子的CAT濃度明顯升高,但CAT基因-262C→T多態性對癡呆并未表現出保護作用[50,51,52]。CAT酶活力下降可誘發記憶衰退[53,54]。GSH濃度在衰老大鼠的額葉皮層、紋狀體中腦和小腦中明顯下降[55]。腦GSH水平低被認為是神經退化性疾病發生的原因之一[56]。

      3.6 、表觀遺傳因素

      容易被忽視的另一個甲醛產生途徑是:個別基因脫甲基或整體DNA的低甲基化,而DNA脫甲基可產生甲醛[28,32,33,34]。如在APP轉基因鼠中,APP基因的不斷脫甲基,實現過度表達,這伴隨著甲醛的產生;同時,Aβ可抑制ADH3的活力,這也可能是甲醛在APP轉基因鼠癡呆模型中蓄積的另一原因。該癡呆模型鼠6月齡時腦內Aβ大量產生,并伴隨甲醛急劇蓄積[6]。另外,正常衰老過程中的腦組織全基因組DNA甲基化水平降低[57],慢性髓性白血病、宮頸癌、前列腺癌和肝癌等癌癥組織中的DNA也呈低甲基化水平[58]。DNA的低甲基化導致甲醛的產生,因此離體培養的腫瘤細胞DNA脫甲基誘發甲醛水平上升3倍以上[37]。

      4、 生理濃度甲醛調控長時程增強(long-term potentiation,LTP)和記憶形成

      學習活動能誘發海馬甲醛濃度的上升,此時產生的甲醛是LTP和空間記憶形成所必需的,提示甲醛可能作為信號分子參與記憶的形成。

      4.1、 學習活動誘發海馬中甲醛產生

      近期的研究顯示,大鼠進行水迷宮訓練后或在體海馬CA1區給予高頻刺激(200 Hz,3 trains,20 pulses)后,海馬甲醛濃度上升至0.06~0.08 mmol/L[35]。而該濃度的甲醛的來源機制很少有報道。有許多酶調節內源性甲醛的產生,如DNA脫甲基化酶[59]、組蛋白脫甲基化酶(histone demethylases,HDMs)、賴氨酸-特異性脫甲基化酶(lysine-specific demethylase 1,LSD1)[60]和線粒體細胞色素P450酶[3]。Guo等研究顯示,電刺激能夠誘發海馬約3%的整體DNA脫甲基化,位于神經元核內的DNA脫甲基化酶是外界刺激后神經元內甲醛濃度上升的關鍵酶[61]。在DNA脫甲基化酶或其他相關酶的介導下,DNA的脫甲基可導致甲醛的產生[32,59,62,63]。DNA脫甲基藥物5-Aza-2’-deoxycytidine可以抑制DNA甲基轉移酶的活性,誘發整體DNA脫甲基化、甲醛的產生[35,64]。以上研究表明,學習活動的刺激可誘發海馬神經元DNA脫甲基,導致甲醛的產生。

      4.2、 內源性甲醛調控LTP和記憶

      Tong等研究顯示,0.08 mmol/L的甲醛能增強N-甲基-D-天冬氨酸(N-methylD-aspartate,NMDA)受體活力,加強海馬LTP的形成[18]。而向側腦室注射FDH,大鼠海馬LTP明顯受抑,并伴隨大鼠的空間記憶缺失[35]。相反,在32月齡的老年大鼠海馬中測得的甲醛濃度是0.5 mmol/L,而向健康大鼠側腦室注射0.5mmol/L甲醛可顯著抑制海馬LTP的形成。同樣,側腦室注射甲醛降解酶的抑制劑如琥珀酸(ADH3抑制劑)或daidzin(ALDH2抑制劑),可引起海馬中的甲醛急劇蓄積,并抑制海馬LTP的形成[18]。以上研究表明,內源性甲醛濃度對LTP和空間記憶的形成有重要作用。

      5 、病理濃度甲醛破壞短期記憶

      伴隨年齡增加,海馬中甲醛逐步蓄積。而過多的甲醛引發的損害作用有:阻斷NMDA受體,破壞海馬LTP形成;降低記憶相關蛋白表達NR2B、SNAP25、VAMP2突觸蛋白的表達,減弱突觸功能;誘發儲存短期記憶的海馬神經元死亡;降低海馬內去甲腎上腺素水平[65];減少腦內褪黑素,引起海馬強烈的氧化應激[66],以上多重作用可導致短期記憶下降或學習困難。

      5.1、 甲醛阻斷NMDA受體破壞LTP形成

      NMDA受體廣泛分布于中樞神經系統。一般認為NRl和NR2亞基組裝在一起,形成NRl/NR2的聚合體。兩個亞單位共同圍繞成離子通道,對學習和記憶起決定性作用[67]。研究顯示,敲除NMDA受體NR2B基因后小鼠記憶能力下降[68],而過表達NR2B可使小鼠、大鼠記憶明顯增高[69,70,71]。老年大鼠腦內NR2B m RNA和蛋白表達均明顯下調,伴隨學習記憶障礙[72]。Zhao等研究顯示,24月齡老年F344大鼠大腦前扣帶皮層中NR2B受體的數量顯著降低,恐懼記憶無法形成[73]。而癡呆早期患者海馬和內嗅皮層NR2A、NR2B受體的表達明顯下調[74]。甲醛能通過NMDA受體影響谷氨酸的突觸傳遞[75],提示NMDA受體可能是甲醛作用的靶點。通過氧化還原NMDA受體亞基NR1和NR2B上半胱氨酸組成的二硫鍵可調節NMDA誘發的電流[76,77,78,79]。甲醛能自發地與游離的半胱氨酸發生化學反應[80,81,82],也能與多種蛋白上的半胱氨酸殘基發生化學反應[83,84,85]。病理濃度甲醛可抑制表達在CHO細胞上的NR1/NR2B介導的內鈣上升,抑制大鼠海馬LTP,破壞大鼠空間記憶的形成[18]。綜合上述研究可見,甲醛可能通過化學反應作用于NMDA受體,破壞LTP形成。

      5.2 、甲醛降低突觸蛋白表達減弱突觸功能

      雖然急性低濃度甲醛暴露后小鼠海馬區NR2A和NR2B表達變化不大[86],但是中等濃度甲醛(3.0 mg/m[3])的吸入后NR2B的表達減少[87]、DNA甲基轉移酶(DNA methyltransferases,DNMTs)活力降低[88]。病理濃度甲醛可通過抑制DNMTs活力下調NR2B的表達[18]。癡呆患者尸檢結果顯示海馬中甲醛蓄積[6],NR2B表達下調[72,74]。SNAP25和VAMP2是表達在海馬和皮層參與學習和記憶的突觸蛋白[89,90,91],隨年齡增大,這兩個突觸蛋白的表達減少,伴隨記憶下降[92,93]。研究顯示甲醛暴露可誘發大鼠海馬中SNAP25和VAMP2蛋白表達下調[94]、空間記憶能力下降[95]。以上研究表明,甲醛可下調突觸蛋白的表達,減弱與學習相關的突觸的活力。

      5.3 、甲醛破壞短期記憶形成的腦區——海馬

      大量的研究表明,甲醛可誘發海馬神經元的死亡[14,75,96,97]。甲醛有較強的水溶性和脂溶性,能透過血腦屏障和細胞膜[98],因此甲醛暴露可導致腦中甲醛迅速擴散、滲透,從而升高腦內甲醛濃度[99]。研究顯示,腹腔注射0.5μmol甲醛,大鼠腦中甲醛迅速上升,說明甲醛具有相當的滲透性,而天然的甲醛消除劑白藜蘆醇可以降低SAMP8小鼠海馬甲醛濃度[18,65]。同時,病理濃度甲醛能誘發tau和amyloid蛋白聚集,誘發癡呆早期海馬神經元的死亡[100,101]。臨床研究顯示,海馬受損是癡呆記憶衰退最早的臨床特征,而海馬是短期記憶形成和暫時存儲的關鍵部位[102]。以上研究表明,強溶解性的甲醛可以穿透細胞膜,造成海馬神經元死亡,破壞記憶的形成與儲存。

      6 、病理濃度甲醛破壞長期記憶

      慢性蓄積的病理濃度甲醛可能通過破壞神經元的軸突髓鞘,阻斷了神經核團間通訊、氧化損傷編碼蛋白的DNA(包括DNA的甲基化減少)、誘發儲存長期記憶的皮層神經元死亡等多重機制,引起長期記憶丟失。

      6.1 、甲醛破壞神經回路——軸突髓鞘

      基礎和臨床研究都顯示,甲醛暴露可導致記憶丟失[9,12,103]。甲醛可誘發神經纖維絲蛋白變性、神經元脫髓鞘[8],而神經元脫髓鞘是癡呆患者尸檢時常常觀察到的病理現象[104,105,106,107],這和多發性硬化疾病相類似[108,109]。轉基因癡呆模型小鼠腦皮層灰質具有多發脫髓鞘現象[110,111]。神經元的脫髓鞘導致神經沖動傳導受損,使神經核團間通訊受阻,從而引起記憶的提取失敗,而深部腦刺激(deep brain stimulation,DBS)能暫時恢復部分神經核團間聯系,使記憶涌現[112,113,114,115]。甲醛消除劑白藜蘆醇有保護神經元髓鞘作用[116,117]。以上研究提示,消除腦內甲醛,保護神經元髓鞘,對于阻止記憶損傷可能具有可行性。

      6.2 、甲醛破壞記憶信息編碼器——DNA

      近幾年來,Neuron、Nature和Science期刊相繼發表DNA甲基化與記憶形成、長期記憶維持關系的論文,使之迅速成為神經科學家關注的熱點。長期記憶的形成,需要DNA脫甲基、轉錄、翻譯出記憶相關蛋白,其中DNA的甲基化是記憶形成的關鍵步驟[118,119,120,121,122]。巧合的是,誘發甲醛蓄積和記憶丟失的因素,如老化[57,123]、汞污染[124,125,126]、殺蟲劑DDT[127]、鉛污染[128]等,都能顯著降低腦DNA甲基化水平。同樣,對癡呆患者尸檢結果顯示大腦皮層總DNA甲基化水平下降[129,130,131,132]。Tong等研究顯示,病理濃度甲醛明顯降低DNA甲基化水平,并使記憶下降[35]。癡呆患者血液淋巴細胞、AD患者的海馬和皮層神經元DNA受到活性氧攻擊導致鏈斷裂,出現DNA-DNA和DNA-蛋白質交聯[133,134,135]。吸入病理濃度甲醛會造成大鼠和小鼠鼻黏膜細胞DNA的N(2)-hydroxymethyl-dG monoadducts和d G-d G發生交聯,導致DNA復制時堿基錯配,誘發突變與癌癥[136,137,138,139]。以上研究表明,病理濃度的甲醛可破已經形成的DNA甲基化譜,從而擦去已經形成的長期記憶。

      6.3 、甲醛破壞長期記憶儲存器——皮層

      大量研究顯示甲醛誘發皮層神經元死亡[11,94,140]。病理濃度甲醛(0.5 mmol/L)顯著抑制線粒體細胞色素酶活力,降低離體培養的皮層神經元代謝能力[141]。0.3mmol/L甲醛對膠質細胞活力影響不大,但可誘發離體培養的皮層神經元死亡[142,143,144]。皮層是記憶儲存的地方,臨床研究顯示,手術切去皮層內側顳葉系統的患者出現遠期記憶喪失等癥狀[145,146]。癡呆患者晚期顳葉系統受損嚴重,出現逆行遺忘、遠期記憶喪失[147,148,149]。Tong等研究顯示癡呆患者尿液中甲醛濃度是隨癡呆程度加深而升高[6]。在癡呆的晚期,體內蓄積過多的甲醛能促進Aβ42形成淀粉樣聚集的老年斑,同時誘發tau蛋白的聚集、皮層神經元死亡[100,101]。

      甲醛易與蛋白的半胱氨酸(cysteine,C)、賴氨酸(lysine,K)等位點結合[84,150]。可誘發蛋白交聯,破壞蛋白的結構,影響蛋白的功能[151]。最新研究顯示,學習活動誘發的瞬間升高的甲醛可作用于NR2B受體的C232位點,增強NMDA受體的激活,提高記憶;而病理濃度的甲醛可交聯NR1的C79位點和NR2B的K79位點,關閉NMDA受體,減少NMDA激活的電流,破壞記憶的形成[152](圖2)。

      圖2.不同濃度甲醛對NMDA電流的影響
     圖2.不同濃度甲醛對NMDA電流的影響

      Fig.2.Effects of different concentrations of formaldehyde(FA)on N-methyl-D-aspartic acid(NMDA)current.Endogenous FA enhances NMDA-currents by binding to C232 of NR2B,whereas excess FA suppresses NMDA-currents by cross-linking C79 of NR1 and K79 of NR2B.F;NMDA-R,NMDA receptor;LTP,long-term potentiation.The figure was reproduced from reference[152].

      7、 總結和展望

      甲醛作為地球上最早出現的有機小分子之一,在機體內參與了生理和病理活動。在生理條件下,學習活動誘可發腦甲醛濃度呈現一定程度瞬時的上升,參與記憶的形成,表明內源性甲醛可調控記憶功能。而當內源甲醛代謝失衡時,如中風(SSAO酶活力增強)、衰老(甲醛降解酶活力降低)、癌癥(DNA脫甲基增強)、糖尿病(ALDH2基因突變)及神經退行性疾病發生時,腦內甲醛濃度異常升高,破壞記憶的形成和提取。這些研究結果提示我們,對于阿爾茨海默病及其他認知障礙相關疾病,可能通過調整腦內甲醛的代謝來改善記憶丟失等癥狀,這給相關疾病治療藥物的研發提供了新思路、新策略。

      參考文獻

      [1]Pinto JP,Gladstone GR,Yung YL.Photochemical production of formaldehyde in Earth’s primitive atmosphere.Science 1980;210(4466):183-185.
      [2]Zhuo M,Small SA,Kandel ER,Hawkins RD.Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus.Science 1993;260(5116):1946-1950.
      [3]Kalasz H.Biological role of formaldehyde,and cycles related to methylation,demethylation,and formaldehyde production.Mini Rev Med Chem 2003;3(3):175-192.
      [4]Heck HD,White EL,Casanova-Schmitz M.Determination of formaldehyde in biological tissues by gas chromatography/mass spectrometry.Biomed Mass Spectrom 1982;9(8):347-353.
      [5]Tong ZQ(童志前),Wan Y,Luo WH,He RQ.Endogenous formaldehyde and related major human diseases.Prog Nat Sci(自然科學進展)2008(11):1201-1210(in Chinese with English abstract).
      [6]Tong Z,Zhang J,Luo W,Wang W,Li F,Li H,Luo H,Lu J,Zhou J,Wan Y,He R.Urine formaldehyde level is inversely correlated to mini mental state examination scores in senile dementia.Neurobiol Aging 2011;32(1):31-41.
      [7]Kilburn KH,Warshaw R,Thornton JC.Formaldehyde impairs memory,equilibrium,and dexterity in histology technicians:effects which persist for days after exposure.Arch Environ Health 1987;42(2):117-120.
      [8]Perna RB,Bordini EJ,Deinzer-Lifrak M.A case of claimed persistent neuropsychological sequelae of chronic formaldehyde exposure:clinical,psychometric,and functional findings.Arch Clin Neuropsychol 2001;16(1):33-44.
      [9]Malek FA,Moritz KU,Fanghanel J.Formaldehyde inhalation&open field behaviour in rats.Indian J Med Res 2003;118:90-96.
      [10]Aslan H,Songur A,Tunc AT,Ozen OA,Bas O,Yagmurca M,Turgut M,Sarsilmaz M,Kaplan S.Effects of formaldehyde exposure on granule cell number and volume of dentate gyrus:a histopathological and stereological study.Brain Res 2006;1122(1):191-200.
      [11]Gurel A,Coskun O,Armutcu F,Kanter M,Ozen OA.Vitamin E against oxidative damage caused by formaldehyde in frontal cortex and hippocampus:biochemical and histological studies.J Chem Neuroanat 2005;29(3):173-178.
      [12]Lu Z,Li CM,Qiao Y,Yan Y,Yang X.Effect of inhaled formaldehyde on learning and memory of mice.Indoor Air 2008;18(2):77-83.
      [13]Feng YJ(馮丫娟),Ding SS,Zhai JX.Effect of vitamin e against impairment on learning and memory ability of mice caused by formaldehyde.Mod Preventive Med(現代預防醫學)2009;36(10):1833-1835(in Chinese with English abstract).
      [14]Li YQ(李一喬),Chen HH,Yin YF,Han F,Ye XS,Ling SC.Formaldehyde inhalation may damage olfactory bulb and hippocampus in rats.J Zhejiang Univ(Med Sci)(浙江大學學報醫學版)2010;39(03):272-277(in Chinese with English abstract).
      [15]Liao S(廖雙),Jiang L,Zhang XP.Effects of inhaled formaldehyde on learning and memory and expression of CaMKII in hippocampus of Wistar rats of different ages.J Chongqing Med Univ(重慶醫科大學學報)2010;35(03):342-345(in Chinese with English abstract).
      [16]Khokhlov AP,Zavalishin IA,Savchenko Iu N,Dziuba AN.Disorders of formaldehyde metabolism and its metabolic precursors in patients with multiple sclerosis.Zh Nevropatol Psikhiatr Im S S Korsakova 1989;89(2):45-48(in Russian with English abstract)
      [17]Conaway CC,Whysner J,Verna LK,Williams GM.Formaldehyde mechanistic data and risk assessment:endogenous protection from DNA adduct formation.Pharmacol Ther 1996;71(1-2):29-55.
      [18]Tong Z,Han C,Luo W,Wang X,Li H,Luo H,Zhou J,Qi J,He R.Accumulated hippocampal formaldehyde induces age-dependent memory decline.Age(Dordr)2013;35(3):583-596.
      [19]Qiang M,Xiao R,Su T,Wu BB,Tong ZQ,Liu Y,He RQ.A novel mechanism for endogenous formaldehyde elevation in SAMP8 mouse.J Alzheimers Dis 2014;40(4):1039-1053.
      [20]Tan T,Zhang Y,Luo W,Lv J,Han C,Hamlin JNR,Luo H,Li H,Wan Y,Yang X,Song W,Tong Z.Formaldehyde induces diabetes-associated cognitive impairments.FASEB J 2018;32(7):3669-3679.
      [21]Mori O,Haseba T,Kameyama K,Shimizu H,Kudoh M,Ohaki O,Arai Y,Yamazaki M,Asano G.Histological distribution of class III alcohol dehydrogenase in human brain.Brain Res 2000;852(1):186-190.
      [22]Uotila L,Koivusalo M.Expression of formaldehyde dehydrogenase and S-formylglutathione hydrolase activities in different rat tissues.Adv Exp Med Biol 1997;414:365-371.
      [23]Mukerjee N,Pietruszko R.Human mitochondrial aldehyde dehydrogenase substrate specificity:comparison of esterase with dehydrogenase reaction.Arch Biochem Biophys 1992;299(1):23-29.
      [24]Dicker E,Cederbaum AI.Inhibition of the low-Km mitochondrial aldehyde dehydrogenase by diethyl maleate and phorone in vivo and in vitro.Implications for formaldehyde metabolism.Biochem J 1986;240(3):821-827.
      [25]Ohta S,Ohsawa I.Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer’s disease:on defects in the cytochrome c oxidase complex and aldehyde detoxification.J Alzheimers Dis 2006;9(2):155-166.
      [26]Murta GL,Campos KK,Bandeira AC,Diniz MF,Costa Gde P,Costa DC,Talvani A,Lima WG,Bezerra FS.Oxidative effects on lung inflammatory response in rats exposed to different concentrations of formaldehyde.Environ Pollut 2016;211:206-213.
      [27]Tralau T,Lafite P,Levy C,Combe JP,Scrutton NS,Leys D.An internal reaction chamber in dimethylglycine oxidase provides efficient protection from exposure to toxic formaldehyde.JBiol Chem 2009;284(26):17826-17834.
      [28]Trewick SC,Henshaw TF,Hausinger RP,Lindahl T,Sedgwick B.Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.Nature 2002;419(6903):174-178.
      [29]Tsujikawa K,Koike K,Kitae K,Shinkawa A,Arima H,Suzuki T,Tsuchiya M,Makino Y,Furukawa T,Konishi N,Yamamoto H.Expression and sub-cellular localization of human ABHfamily molecules.J Cell Mol Med 2007;11(5):1105-1116.
      [30]Luka Z,Pakhomova S,Loukachevitch LV,Calcutt MW,Newcomer ME,Wagner C.Crystal structure of the histone lysine specific demethylase LSD1 complexed with tetrahydrofolate.Protein Sci 2014;23(7):993-998.
      [31]Liu J,Liu FY,Tong ZQ,Li ZH,Chen W,Luo WH,Li H,Luo HJ,Tang Y,Tang JM,Cai J,Liao FF,Wan Y.Lysine-specific demethylase 1 in breast cancer cells contributes to the production of endogenous formaldehyde in the metastatic bone cancer pain model of rats.PLoSOne 2013;8(3):e58957.
      [32]Gerken T,Girard CA,Tung YC,Webby CJ,Saudek V,Hewitson KS,Yeo GS,McDonough MA,Cunliffe S,McNeill LA,Galvanovskis J,Rorsman P,Robins P,Prieur X,Coll AP,Ma M,Jovanovic Z,Farooqi IS,Sedgwick B,Barroso I,Lindahl T,Ponting CP,Ashcroft FM,O'Rahilly S,Schofield CJ.The obesity-associated FTO gene encodes a 2-oxoglutaratedependent nucleic acid demethylase.Science 2007;318(5855):1469-1472.
      [33]Roy TW,Bhagwat AS.Kinetic studies of Escherichia coli Alk B using a new fluorescencebased assay for DNA demethylation.Nucleic Acids Res 2007;35(21):e147.
      [34]Yi C,Yang CG,He C.A non-heme iron-mediated chemical demethylation in DNA and RNA.Acc Chem Res 2009;42(4):519-529.
      [35]Tong Z,Han C,Luo W,Li H,Luo H,Qiang M,Su T,Wu B,Liu Y,Yang X,Wan Y,Cui D,He R.Aging-associated excess formaldehyde leads to spatial memory deficits.Sci Rep 2013;3:1807.
      [36]Trezl L,Rusznak I,Tyihak E,Szarvas T,Szende B.Spontaneous Nε-methylation and Nε-formylation reactions between L-lysine and formaldehyde inhibited by L-ascorbic acid.Biochem J 1983;214(2):289-292.
      [37]Thorndike J,Beck WS.Production of formaldehyde from N5-methyltetrahydrofolate by normal and leukemic leukocytes.Cancer Res 1977;37(4):1125-1132.
      [38]Spanel P,Smith D,Holland TA,Al Singary W,Elder JB.Analysis of formaldehyde in the headspace of urine from bladder and prostate cancer patients using selected ion flow tube mass spectrometry.Rapid Commun Mass Spectrom 1999;13(14):1354-1359.
      [39]Ebeler SE,Clifford AJ,Shibamoto T.Quantitative analysis by gas chromatography of volatile carbonyl compounds in expired air from mice and human.J Chromatogr B Biomed Sci Appl1997;702(1-2):211-215.
      [40]Tong Z,Luo W,Wang Y,Yang F,Han Y,Li H,Luo H,Duan B,Xu T,Maoying Q,Tan H,Wang J,Zhao H,Liu F,Wan Y.Tumor tissue-derived formaldehyde and acidic microenvironment synergistically induce bone cancer pain.PLoS One 2010;5(4):e10234.
      [41]Li HS(李海山),Dai YF,Huang HL,Sun YF.Polymorphisms of aldehyde and alcohol dehydrogenase genes associated with susceptibility to trichloroethylene-induced medicamentosa-like dermatitis.J Hyg Res(衛生研究)2006;35(2):149-151(in Chinese with English abstract).
      [42]Thomasson HR,Edenberg HJ,Crabb DW,Mai XL,Jerome RE,Li TK,Wang SP,Lin YT,Lu RB,Yin SJ.Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.Am J Hum Genet 1991;48(4):677-681.
      [43]Deltour L,Foglio MH,Duester G.Metabolic deficiencies in alcohol dehydrogenase Adh1,Adh3,and Adh4 null mutant mice.Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid.J Biol Chem 1999;274(24):16796-16801.
      [44]Hou Q,Jiang H,Zhang X,Guo C,Huang B,Wang P,Wang T,Wu K,Li J,Gong Z,Du L,Liu Y,Liu L,Chen C.Nitric oxide metabolism controlled by formaldehyde dehydrogenase(fdh,homolog of mammalian GSNOR)plays a crucial role in visual pattern memory in Drosophila.Nitric Oxide 2011;24(1):17-24.
      [45]Kamino K,Nagasaka K,Imagawa M,Yamamoto H,Yoneda H,Ueki A,Kitamura S,Namekata K,Miki T,Ohta S.Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer’s disease in the Japanese population.Biochem Biophys Res Commun2000;273(1):192-196.
      [46]Wang B,Wang J,Zhou S,Tan S,He X,Yang Z,Xie YC,Li S,Zheng C,Ma X.The association of mitochondrial aldehyde dehydrogenase gene(ALDH2)polymorphism with susceptibility to late-onset Alzheimer’s disease in Chinese.J Neurol Sci 2008;268(1-2):172-175.
      [47]Wang RS,Nakajima T,Kawamoto T,Honma T.Effects of aldehyde dehydrogenase-2 genetic polymorphisms on metabolism of structurally different aldehydes in human liver.Drug Metab Dispos 2002;30(1):69-73.
      [48]Nakashima Y,Ohsawa I,Konishi F,Hasegawa T,Kumamoto S,Suzuki Y,Ohta S.Preventive effects of Chlorella on cognitive decline in age-dependent dementia model mice.Neurosci Lett2009;464(3):193-198.
      [49]Ohsawa I,Nishimaki K,Murakami Y,Suzuki Y,Ishikawa M,Ohta S.Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity.J Neurosci 2008;28(24):6239-6249.
      [50]Capurso C,Solfrizzi V,D'Introno A,Colacicco AM,Capurso SA,Bifaro L,Menga R,Santamato A,Seripa D,Pilotto A,Capurso A,Panza F.Short arm of chromosome 11 and sporadic Alzheimer’s disease:catalase and cathepsin D gene polymorphisms.Neurosci Lett2008;432(3):237-242.
      [51]Goulas A,Fidani L,Kotsis A,Mirtsou V,Petersen RC,Tangalos E,Hardy J.An association study of a functional catalase gene polymorphism,-262C-->T,and patients with Alzheimer’s disease.Neurosci Lett 2002;330(2):210-213.
      [52]Kim TH,Hong JM,Oh B,Cho YS,Lee JY,Kim HL,Shin ES,Lee JE,Park EK,Kim SY.Genetic association study of polymorphisms in the catalase gene with the risk of osteonecrosis of the femoral head in the Korean population.Osteoarthritis Cartilage 2008;16(9):1060-1066.
      [53]Liu R,Liu IY,Bi X,Thompson RF,Doctrow SR,Malfroy B,Baudry M.Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics.Proc Natl Acad Sci U S A 2003;100(14):8526-8531.
      [54]Manrique HM,Miquel M,Aragon CM.Brain catalase mediates potentiation of social recognition memory produced by ethanol in mice.Drug Alcohol Depend 2005;79(3):343-350.
      [55]Zhu Y,Carvey PM,Ling Z.Age-related changes in glutathione and glutathione-related enzymes in rat brain.Brain Res 2006;1090(1):35-44.
      [56]Gironi M,Bianchi A,Russo A,Alberoni M,Ceresa L,Angelini A,Cursano C,Mariani E,Nemni R,Kullmann C,Farina E,Martinelli Boneschi F.Oxidative imbalance in different neurodegenerative diseases with memory impairment.Neurodegener Dis 2011;8(3):129-137.
      [57]Liu L,van Groen T,Kadish I,Tollefsbol TO.DNA methylation impacts on learning and memory in aging.Neurobiol Aging 2009;30(4):549-560.
      [58]Ehrlich M.DNA hypomethylation in cancer cells.Epigenomics 2009;1(2):239-259.
      [59]Patra SK,Patra A,Rizzi F,Ghosh TC,Bettuzzi S.Demethylation of(Cytosine-5-C-methyl)DNA and regulation of transcription in the epigenetic pathways of cancer development.Cancer Metastasis Rev 2008;27(2):315-334.
      [60]Shi Y,Lan F,Matson C,Mulligan P,Whetstine JR,Cole PA,Casero RA,Shi Y.Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.Cell 2004;119(7):941-953.
      [61]Guo JU,Ma DK,Mo H,Ball MP,Jang MH,Bonaguidi MA,Balazer JA,Eaves HL,Xie B,Ford E,Zhang K,Ming GL,Gao Y,Song H.Neuronal activity modifies the DNA methylation landscape in the adult brain.Nat Neurosci 2011;14(10):1345-1351.
      [62]Freiherr J,Hallschmid M,Frey WH,2nd,Brunner YF,Chapman CD,Holscher C,Craft S,De Felice FG,Benedict C.Intranasal insulin as a treatment for Alzheimer’s disease:a review of basic research and clinical evidence.CNS Drugs 2013;27(7):505-514.
      [63]Cervoni N,Bhattacharya S,Szyf M.DNA demethylase is a processive enzyme.J Biol Chem1999;274(13):8363-8366.
      [64]Hamm CA,Xie H,Costa FF,Vanin EF,Seftor EA,Sredni ST,Bischof J,Wang D,Bonaldo MF,Hendrix MJ,Soares MB.Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2’-deoxycytidine results in increased tumorigenicity.PLoS One 2009;4(12):e8340.
      [65]Mei Y,Jiang C,Wan Y,Lv J,Jia J,Wang X,Yang X,Tong Z.Aging-associated formaldehydeinduced norepinephrine deficiency contributes to age-related memory decline.Aging Cell 2015;14(4):659-668.
      [66]Mei Y,Duan C,Li X,Zhao Y,Cao F,Shang S,Ding S,Yue X,Gao G,Yang H,Shen L,Feng X,Jia J,Tong Z,Yang X.Reduction of endogenous melatonin accelerates cognitive decline in mice in a simulated occupational formaldehyde exposure environment.Int J Environ Res Public Health 2016;13(3).pii:E258.doi:10.3390/ijerph13030258.
      [67]Furukawa H,Singh SK,Mancusso R,Gouaux E.Subunit arrangement and function in NMDAreceptors.Nature 2005;438(7065):185-192.
      [68]Clayton DA,Mesches MH,Alvarez E,Bickford PC,Browning MD.A hippocampal NR2Bdeficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat.J Neurosci 2002;22(9):3628-3637.
      [69]Tang YP,Shimizu E,Dube GR,Rampon C,Kerchner GA,Zhuo M,Liu G,Tsien JZ.Genetic enhancement of learning and memory in mice.Nature 1999;401(6748):63-69.
      [70]Mallon AP,Auberson YP,Stone TW.Selective subunit antagonists suggest an inhibitory relationship between NR2B and NR2A-subunit containing N-methyl-D-aspartate receptors in hippocampal slices.Exp Brain Res 2005;162(3):374-383.
      [71]Wang D,Cui Z,Zeng Q,Kuang H,Wang LP,Tsien JZ,Cao X.Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats.PLoSOne 2009;4(10):e7486.
      [72]Clayton DA,Browning MD.Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats.Neurobiol Aging 2001;22(1):165-168.
      [73]Zhao MG,Toyoda H,Lee YS,Wu LJ,Ko SW,Zhang XH,Jia Y,Shum F,Xu H,Li BM,Kaang BK,Zhuo M.Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory.Neuron 2005;47(6):859-872.
      [74]Bi H,Sze CI.N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer’s disease.J Neurol Sci 2002;200(1-2):11-18.
      [75]Ahmed S,Tsukahara S,Tin Tin Win S,Yamamoto S,Kunugita N,Arashidani K,Fujimaki H.Effects of low-level formaldehyde exposure on synaptic plasticity-related gene expression in the hippocampus of immunized mice.J Neuroimmunol 2007;186(1-2):104-111.
      [76]Brimecombe JC,Boeckman FA,Aizenman E.Functional consequences of NR2 subunit composition in single recombinant N-methyl-D-aspartate receptors.Proc Natl Acad Sci U S A1997;94(20):11019-11024.
      [77]Herin GA,Du S,Aizenman E.The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site.J Neurochem 2001;78(6):1307-1314.
      [78]Popescu G.Mechanism-based targeting of NMDA receptor functions.Cell Mol Life Sci 2005;62(18):2100-2111.
      [79]Sullivan JM,Traynelis SF,Chen HS,Escobar W,Heinemann SF,Lipton SA.Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor.Neuron 1994;13(4):929-936.
      [80]Kallen RG.Equilibria for the reaction of cysteine and derivatives with formaldehyde and protons.J Am Chem Soc 1971;93(23):6227-6235.
      [81]Kallen RG.The mechanism of reactions involving Schiff base intermediates.Thiazolidine formation from L-cysteine and formaldehyde.J Am Chem Soc 1971;93(23):6236-6248.
      [82]Mackenzie CG,Harris J.N-formylcysteine synthesis in mitochondria from formaldehyde and L-cysteine via thiazolidinecarboxylic acid.J Biol Chem 1957;227(1):393-406.
      [83]Metz B,Kersten GF,Baart GJ,de Jong A,Meiring H,ten Hove J,van Steenbergen MJ,Hennink WE,Crommelin DJ,Jiskoot W.Identification of formaldehyde-induced modifications in proteins:reactions with insulin.Bioconjug Chem 2006;17(3):815-822.
      [84]Metz B,Kersten GF,Hoogerhout P,Brugghe HF,Timmermans HA,de Jong A,Meiring H,ten Hove J,Hennink WE,Crommelin DJ,Jiskoot W.Identification of formaldehyde-induced modifications in proteins:reactions with model peptides.J Biol Chem 2004;279(8):6235-6243.
      [85]Toews J,Rogalski JC,Clark TJ,Kast J.Mass spectrometric identification of formaldehydeinduced peptide modifications under in vivo protein cross-linking conditions.Anal Chim Acta2008;618(2):168-183.
      [86]Tsukahara S,Yamamoto S,Tin Tin Win S,Ahmed S,Kunugita N,Arashidani K,Fujimaki H.Inhalation of low-level formaldehyde increases the Bcl-2/Bax expression ratio in the hippocampus of immunologically sensitized mice.Neuroimmunomodulation 2006;13(2):63-68.
      [87]Ke K(柯珂),Zhu Y,Qiao Y,Peng GY,Xu Q,Yang X.Effects of inhaled formaldehyde on the transcription of NMDA-R gene in mice fore cerebrum.Acta Sci Circumst(環境科學學報)2007(02):282-288(in Chinese with English abstract).
      [88]Lee S,Kim W,Ham BJ,Chen W,Bear MF,Yoon BJ.Activity-dependent NR2B expression is mediated by MeCP2-dependent epigenetic regulation.Biochem Biophys Res Commun 2008;377(3):930-934.
      [89]Giniatullin AR,Darios F,Shakirzyanova A,Davletov B,Giniatullin R.SNAP25 is a presynaptic target for the depressant action of reactive oxygen species on transmitter release.JNeurochem 2006;98(6):1789-1797.
      [90]Selak S,Paternain AV,Aller MI,Pico E,Rivera R,Lerma J.A role for SNAP25 in internalization of kainate receptors and synaptic plasticity.Neuron 2009;63(3):357-371.
      [91]Soderqvist S,McNab F,Peyrard-Janvid M,Matsson H,Humphreys K,Kere J,Klingberg T.The SNAP25 gene is linked to working memory capacity and maturation of the posterior cingulate cortex during childhood.Biol Psychiatry 2010;68(12):1120-1125.
      [92]Rubino T,Realini N,Braida D,Guidi S,Capurro V,Vigano D,Guidali C,Pinter M,Sala M,Bartesaghi R,Parolaro D.Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood.Hippocampus2009;19(8):763-772.
      [93]VanGuilder HD,Yan H,Farley JA,Sonntag WE,Freeman WM.Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome.J Neurochem 2010;113(6):1577-1588.
      [94]Liu Y,Ye Z,Luo H,Sun M,Li M,Fan D,Chui D.Inhalative formaldehyde exposure enhances aggressive behavior and disturbs monoamines in frontal cortex synaptosome of male rats.Neurosci Lett 2009;464(2):113-116.
      [95]Liu Y,Ye Z,Yang H,Zhou L,Fan D,He S,Chui D.Disturbances of soluble N-ethylmaleimidesensitive factor attachment proteins in hippocampal synaptosomes contribute to cognitive impairment after repetitive formaldehyde inhalation in male rats.Neuroscience 2010;169(3):1248-1254.
      [96]Fujimaki H,Kurokawa Y,Kakeyama M,Kunugita N,Fueta Y,Fukuda T,Hori H,Arashidani K.Inhalation of low-level formaldehyde enhances nerve growth factor production in the hippocampus of mice.Neuroimmunomodulation 2004;11(6):373-375.
      [97]Sarsilmaz M,Kaplan S,Songur A,Colakoglu S,Aslan H,Tunc AT,Ozen OA,Turgut M,Bas O.Effects of postnatal formaldehyde exposure on pyramidal cell number,volume of cell layer in hippocampus and hemisphere in the rat:a stereological study.Brain Res 2007;1145:157-167.
      [98]Gronvall JL,Garpenstrand H,Oreland L,Ekblom J.Autoradiographic imaging of formaldehyde adducts in mice:possible relevance for vascular damage in diabetes.Life Sci 1998;63(9):759-768.
      [99]Cui X.Inhaled formaldehyde on the effects of GSH level and distribution of formaldehyde.1996.
      [100]Nie CL,Wei Y,Chen X,Liu YY,Dui W,Liu Y,Davies MC,Tendler SJ,He RG.Formaldehyde at low concentration induces protein tau into globular amyloid-like aggregates in vitro and in vivo.PLoS One 2007;2(7):e629.
      [101]Chen K,Maley J,Yu PH.Potential inplications of endogenous aldehydes in beta-amyloid misfolding,oligomerization and fibrillogenesis.J Neurochem 2006;99(5):1413-1424.
      [102]Squire LR,Bayley PJ.The neuroanatomy of very remote memory.Lancet Neurol 2006;5(2):112-113.
      [103]Marceaux JC,Dilks LS,Hixson S.Neuropsychological effects of formaldehyde use.JPsychoactive Drugs 2008;40(2):207-210.
      [104]Fornari E,Maeder P,Meuli R,Ghika J,Knyazeva MG.Demyelination of superficial white matter in early Alzheimer’s disease:a magnetization transfer imaging study.Neurobiol Aging2012;33(2):428.e427-419.
      [105]Kovari E,Gold G,Herrmann FR,Canuto A,Hof PR,Bouras C,Giannakopoulos P.Cortical microinfarcts and demyelination affect cognition in cases at high risk for dementia.Neurology2007;68(12):927-931.
      [106]Kutzelnigg A,Lassmann H.Cortical demyelination in multiple sclerosis:a substrate for cognitive deficits?J Neurol Sci 2006;245(1-2):123-126.
      [107]Makinodan M,Yamauchi T,Tatsumi K,Okuda H,Takeda T,Kiuchi K,Sadamatsu M,Wanaka A,Kishimoto T.Demyelination in the juvenile period,but not in adulthood,leads to long-lasting cognitive impairment and deficient social interaction in mice.Prog Neuropsychopharmacol Biol Psychiatry 2009;33(6):978-985.
      [108]Geurts JJ,Bo L,Roosendaal SD,Hazes T,Daniels R,Barkhof F,Witter MP,Huitinga I,van der Valk P.Extensive hippocampal demyelination in multiple sclerosis.J Neuropathol Exp Neurol 2007;66(9):819-827.
      [109]Mineev KK,Prakhova LN,Il'ves AG,Kataeva GV,Petrov AM,Reznikova TN,Pozdnyakov AV,Stolyarov ID.Characteristics of neurological and cognitive status in patients with multiple sclerosis in relation to the location and volumes of demyelination foci and the severity of brain atrophy.Neurosci Behav Physiol 2009;39(1):35-38.
      [110]Wakita H,Tomimoto H,Akiguchi I,Matsuo A,Lin JX,Ihara M,McGeer PL.Axonal damage and demyelination in the white matter after chronic cerebral hypoperfusion in the rat.Brain Res2002;924(1):63-70.
      [111]Mitew S,Kirkcaldie MT,Halliday GM,Shepherd CE,Vickers JC,Dickson TC.Focal demyelination in Alzheimer’s disease and transgenic mouse models.Acta Neuropathol 2010;119(5):567-577.
      [112]Hamani C,Dubiela FP,Soares JC,Shin D,Bittencourt S,Covolan L,Carlen PL,Laxton AW,Hodaie M,Stone SS,Ha Y,Hutchison WD,Lozano AM,Mello LE,Oliveira MG.Anterior thalamus deep brain stimulation at high current impairs memory in rats.Exp Neurol 2010;225(1):154-162.
      [113]Hirshler YK,Polat U,Biegon A.Intracranial electrode implantation produces regional neuroinflammation and memory deficits in rats.Exp Neurol 2010;222(1):42-50.
      [114]Hu R,Eskandar E,Williams Z.Role of deep brain stimulation in modulating memory formation and recall.Neurosurg Focus 2009;27(1):E3.
      [115]Laxton AW,Tang-Wai DF,McAndrews MP,Zumsteg D,Wennberg R,Keren R,Wherrett J,Naglie G,Hamani C,Smith GS,Lozano AM.A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease.Ann Neurol 2010;68(4):521-534.
      [116]Markert CD,Kim E,Gifondorwa DJ,Childers MK,Milligan CE.A single-dose resveratrol treatment in a mouse model of amyotrophic lateral sclerosis.J Med Food 2010;13(5):1081-1085.
      [117]Shindler KS,Ventura E,Dutt M,Elliott P,Fitzgerald DC,Rostami A.Oral resveratrol reduces neuronal damage in a model of multiple sclerosis.J Neuroophthalmol 2010;30(4):328-339.
      [118]Day JJ,Sweatt JD.DNA methylation and memory formation.Nat Neurosci 2010;13(11):1319-1323.
      [119]Feng J,Zhou Y,Campbell SL,Le T,Li E,Sweatt JD,Silva AJ,Fan G.Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.Nat Neurosci 2010;13(4):423-430.
      [120]Franklin TB,Mansuy IM.The prevalence of epigenetic mechanisms in the regulation of cognitive functions and behaviour.Curr Opin Neurobiol 2010;20(4):441-449.
      [121]Graff J,Mansuy IM.Epigenetic dysregulation in cognitive disorders.Eur J Neurosci 2009;30(1):1-8.
      [122]Miller CA,Gavin CF,White JA,Parrish RR,Honasoge A,Yancey CR,Rivera IM,Rubio MD,Rumbaugh G,Sweatt JD.Cortical DNA methylation maintains remote memory.Nat Neurosci2010;13(6):664-666.
      [123]Penner MR,Roth TL,Barnes CA,Sweatt JD.An epigenetic hypothesis of aging-related cognitive dysfunction.Front Aging Neurosci 2010;2:9.
      [124]Pilsner JR,Lazarus AL,Nam DH,Letcher RJ,Sonne C,Dietz R,Basu N.Mercury-associated DNA hypomethylation in polar bear brains via the LUminometric Methylation Assay:a sensitive method to study epigenetics in wildlife.Mol Ecol 2010;19(2):307-314.
      [125]Retfalvi T,Nemeth ZI,Sarudi I,Albert L.Alteration of endogenous formaldehyde level following mercury accumulation in different pig tissues.Acta Biol Hung 1998;49(2-4):375-379.
      [126]Tyler DD.The inhibition of phosphate entry into rat liver mitochondria by organic mercurials and by formaldehyde.Biochem J 1968;107(1):121-123.
      [127]Shutoh Y,Takeda M,Ohtsuka R,Haishima A,Yamaguchi S,Fujie H,Komatsu Y,Maita K,Harada T.Low dose effects of dichlorodiphenyltrichloroethane(DDT)on gene transcription and DNA methylation in the hypothalamus of young male rats:implication of hormesis-like effects.J Toxicol Sci 2009;34(5):469-482.
      [128]Pilsner JR,Hu H,Ettinger A,Sanchez BN,Wright RO,Cantonwine D,Lazarus A,LamadridFigueroa H,Mercado-Garcia A,Tellez-Rojo MM,Hernandez-Avila M.Influence of prenatal lead exposure on genomic methylation of cord blood DNA.Environ Health Perspect 2009;117(9):1466-1471.
      [129]Mastroeni D,Grover A,Delvaux E,Whiteside C,Coleman PD,Rogers J.Epigenetic changes in Alzheimer’s disease:decrements in DNA methylation.Neurobiol Aging 2010;31(12):2025-2037.
      [130]Pogribny IP,Beland FA.DNA hypomethylation in the origin and pathogenesis of human diseases.Cell Mol Life Sci 2009;66(14):2249-2261.
      [131]Siegmund KD,Connor CM,Campan M,Long TI,Weisenberger DJ,Biniszkiewicz D,Jaenisch R,Laird PW,Akbarian S.DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons.PLoS One 2007;2(9):e895.
      [132]Fuso A,Nicolia V,Cavallaro RA,Scarpa S.DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer’s disease models.J Nutr Biochem 2011;22(3):242-251.
      [133]Isobe C,Abe T,Terayama Y.Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2’-deoxyguanosine in the CSF of patients with Alzheimer’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process.J Neurol 2010;257(3):399-404.
      [134]Mullaart E,Boerrigter ME,Ravid R,Swaab DF,Vijg J.Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients.Neurobiol Aging 1990;11(3):169-173.
      [135]Kadioglu E,Sardas S,Aslan S,Isik E,Esat Karakaya A.Detection of oxidative DNA damage in lymphocytes of patients with Alzheimer’s disease.Biomarkers 2004;9(2):203-209.
      [136]Liu YR,Zhou Y,Qiu W,Zeng JY,Shen LL,Li AP,Zhou JW.Exposure to formaldehyde induces heritable DNA mutations in mice.J Toxicol Environ Health A 2009;72(11-12):767-773.
      [137]Lu K,Collins LB,Ru H,Bermudez E,Swenberg JA.Distribution of DNA adducts caused by inhaled formaldehyde is consistent with induction of nasal carcinoma but not leukemia.Toxicol Sci 2010;116(2):441-451.
      [138]Szulawska A,Gniazdowski M,Czyz M.Sequence specificity of formaldehyde-mediated covalent binding of anthracycline derivatives to DNA.Biochem Pharmacol 2005;69(1):7-18.
      [139]Bailly C,Goossens JF,Laine W,Anizon F,Prudhomme M,Ren J,Chaires JB.Formaldehydeinduced alkylation of a 2’-aminoglucose rebeccamycin derivative to both A.T and G.C base pairs in DNA.J Med Chem 2000;43(24):4711-4720.
      [140]Zararsiz I,Kus I,Ogeturk M,Akpolat N,Kose E,Meydan S,Sarsilmaz M.Melatonin prevents formaldehyde-induced neurotoxicity in prefrontal cortex of rats:an immunohistochemical and biochemical study.Cell Biochem Funct 2007;25(4):413-418.
      [141]Liu T(劉婷),Bai XT.Effect of formaldehyde on energy metabolism in postnatal rat cortex neurons in culture.J Hyg Res(衛生研究)2005;34(3):275-277(in Chinese with English abstract).
      [142]Dringen R,Gutterer JM,Hirrlinger J.Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species.Eur J Biochem2000;267(16):4912-4916.
      [143]Song MS,Baker GB,Dursun SM,Todd KG.The antidepressant phenelzine protects neurons and astrocytes against formaldehyde-induced toxicity.J Neurochem 2010;114(5):1405-1413.
      [144]Tulpule K,Dringen R.Formaldehyde stimulates Mrp1-mediated glutathione deprivation of cultured astrocytes.J Neurochem 2011;116(4):626-635.
      [145]Wittig JH,Jr.,Jang AI,Cocjin JB,Inati SK,Zaghloul KA.Attention improves memory by suppressing spiking-neuron activity in the human anteror temporal lobe.Nature neuroscience2018;21(6):808-810.
      [146]Dossani RH,Missios S,Nanda A.The legacy of Henry Molaison(1926-2008)and the impact of his bilateral mesial temporal lobe surgery on the study of human memory.World Neurosurg2015;84(4):1127-1135.
      [147]Okada A,Ohyama K,Ueda T.Early-stage right temporal lobe variant of frontotemporal dementia:3 years of follow-up observations.BMJ Case Rep 2018;2018.pii:bcr-2018-224431.doi:10.1136/bcr-2018-224431.
      [148]Tagawa R,Hashimoto H,Nakanishi A,Kawarada Y,Muramatsu T,Matsuda Y,Kataoka K,Shimada A,Uchida K,Yoshida A,Higashiyama S,Kawabe J,Kai T,Shiomi S,Mori H,Inoue K.The relationship between medial temporal lobe atrophy and cognitive impairment in patients with dementia with Lewy bodies.J Geriatr Psychiatry Neurol 2015;28(4):249-254.
      [149]Mansoor Y,Jastrzab L,Dutt S,Miller BL,Seeley WW,Kramer JH.Memory profiles in pathology or biomarker confirmed Alzheimer disease and frontotemporal dementia.Alzheimer Dis Assoc Disord 2015;29(2):135-140.
      [150]Gubisne-Haberle D,Hill W,Kazachkov M,Richardson JS,Yu PH.Protein cross-linkage induced by formaldehyde derived from semicarbazide-sensitive amine oxidase-mediated deamination of methylamine.J Pharmacol Exp Ther 2004;310(3):1125-1132.
      [151]Sutherland BW,Toews J,Kast J.Utility of formaldehyde cross-linking and mass spectrometry in the study of protein-protein interactions.J Mass Spectrom 2008;43(6):699-715.
      [152]Ai L,Tan T,Tang Y,Yang J,Cui D,Wang R,Wang A,Fei X,Di Y,Wang X,Yu Y,Zhao S,Wang W,Bai S,Yang X,He R,Lin W,Han H,Cai X,Tong Z.Endogenous formaldehyde is a memory-related molecule in mice and humans.Commun Biol 2019;2:446.

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