2013 年 08 月 13 日 , , , ,

世界衛生組織指出,失智症中常見的「阿茲海默症」,2010年全球超過3500萬病患,到2030年增加近一倍,台灣部份據統計2012年失智症患者約17萬人,預估2036年30萬人,2056年62萬人,那時你幾歲?在聽起來如此恐怖的敘述之下,眾多科學家投入研究努力阻止災情擴大,最近就有了多項新發現。

發現阿茲海默症嫌犯的始作俑者

堆積在腦部神經元周圍的 β類澱粉蛋白被認為是阿茲海默症的嫌犯之一,加州大學聖地牙哥分校的研究者發現,製造出 β類澱粉蛋白的一種 BACE-1 酵素,會與一種叫做「前類澱粉蛋白質」產生連接,然後將前類澱粉蛋白質切段,因此若能將前類澱粉蛋白質與 BACE-1 分隔開,就可以阻止 β類澱粉蛋白產生。這項研究終於解開過往究竟是誰造成前類澱粉蛋白質被切段的謎題。

這項刊登在最新一期「神經元」期刊(Neuron)的研究,分別在人與老鼠的腦神經元與組織上完成了實驗,他們發現,健康的腦部,前類澱粉蛋白質與 BACE-1 在產生時就保持隔離的狀態,彼此無法產生互動,因此也就不會產生 β類澱粉蛋白。團隊中的 Subhojit Roy 博士就比喻說,把它們分開,就像是讓火柴碰不到火藥,自然就不會爆炸。有了這層認識,就可以創造出阻止阿茲海默症的新視野。

app BACE-1

▲找出方法(圖左兇殘的老師)以隔離前類澱粉蛋白質(APP,圖中)與 BACE-1(圖右),就不會產生 β類澱粉蛋白。(圖片來源: University of California, San Diego School of Medicine)

兩個嫌犯各有其源頭

雖然 Subhojit Roy 的研究解開了一個謎題,但並不代表一切答案,因為除了 β類澱粉蛋白會產生堆積,另一種 tau蛋白質也會。稍早的一份針對1269個樣本 tau蛋白質的研究發現,幾種基因跟它有所關連。華盛頓大學基因與神經學博士 Alison M. Goate 表示,她們測量腦脊液中的 tau蛋白質並確認幾種基因與造成大量 tau蛋白質有關,而其中三種跟 β類澱粉蛋白沒有關連。

至於基因 APOE,過去已經發現它與 β類澱粉蛋白有關,這次研究則發現它能同時影響兩者,有助於解釋基因對阿茲海默症有多大影響。另一方面,在她們研究的樣本中,也發現了某些樣本帶有大量 β類澱粉蛋白,但是卻沒有發展出阿茲海默症,研究者沒有確認其原因,但推論或許這跟 tau蛋白質不足有關。因此,tau蛋白質或可做為一種預測疾病發展的指標,當 tau蛋白質變多,人們就更可能罹患失智症。也可以藉此研發藥物壓低 tau蛋白質的量,從而阻止發病或延緩病情。這項研究刊登在「神經元」期刊。

Tangle and plaque
▲左上角是 tau蛋白質堆積造成的神經纖維糾結,右下角是 β類澱粉蛋白堆積造成的班塊。(圖片來源: Nigel Cairns, PhD)

兩個嫌犯合作成了兇手

另一項研究則對 β類澱粉蛋白與同樣發生堆積情況的 tau蛋白做了近距離觀察,發現原本認為互不相干的兩個嫌犯,其實是共同造成了阿茲海默症。美國奧勒岡健康與科學大學(Oregon Health & Science University) Hemachandra Reddy博士的這項研究指出,當這兩個產生交互作用時,會傷害神經元末端的突觸,這將造成阿茲海默症病患認知功能崩解的後果。

這項刊載在「阿茲海默症」期刊(Journal of Alzheimer’s Disease)的研究,以死去的人類與老鼠患者腦部組織為目標,發現當兩者交互作用愈頻繁,阿茲海默症的病況愈嚴重。利用多重抗體觀察,他們發現 β類澱粉蛋白與 tau蛋白質的複合體,阿茲海默症愈嚴重的,複合體愈多。相對於沒有阿茲海默症的對照組,幾乎沒有複合體出現。他們下一步的研究則是找出 β類澱粉蛋白與 tau蛋白質產生互動的所在,以及抑止他們接觸的方法。

Bacillus amyloliquefaciens
▲本圖模擬兩個嫌犯組成複合體聯手犯案。(圖片來源: Wikimedia Commons)

腦部免疫細胞被兇手放倒

一百多年的阿茲海默醫師在發現阿茲海默症時,就已經發現 β類澱粉蛋白等堆積而成的斑被腦部的免疫細胞─微膠質細胞包圍著,但一百多年來都不清楚是怎麼回事,以及微膠質細胞為何沒有發揮它腦部清道夫的作用。德國醫師 Grietje Krabbe 等人指出,這些圍繞著斑塊的微膠質細胞未能發揮它兩種主要的作用,一種是移除無用的細胞碎片或有害的組織,另一種是快速處理病變的能力。

目前研究者還不清楚微膠質細胞失去作用的其他影響,不過確定這是在阿茲海默症發展早期就受到 β類澱粉蛋白影響的結果,透過 β類澱粉蛋白抗體可以逆轉這個機制、從而降低 β類澱粉蛋白的影響,就是明證。也就是說,如果能找到有效操控微膠質細胞讓它保持作用,就可以阻止阿茲海默症發生。

Microglia_Plaque
▲褐色小點就是微膠質細胞,圍繞著紅色的 β類澱粉蛋白。(圖片來源:Frank Heppner/ Copyright: Charité)

Sleep, Sleep, Sleep……

看完以上這些,你可能會覺得「很重要,但跟我關係不大」,那麼接下來這項研究就很有關係了。同樣是華盛頓大學醫學院的研究指出,睡眠不足的人會有阿茲海默症的早期症狀,但還不會有記憶喪失或認知功能衰退的狀況發生。這項刊載於「美國醫學會神經病學期刊」(JAMA Neurology)的研究,證實了之前睡眠不足與腦中斑塊堆積的關連。

這項研究找來145位45至75歲的志願人士,並且先檢驗了他們的脊髓液,發現其中有32位處於阿茲海默症的潛伏期,還沒有明顯症狀。接著讓這些人在睡眠時手腕上帶著感測器,以紀錄他們睡眠過程中翻身等動作,做為判斷睡眠效率的資料依據。實驗結果顯示,32位處於阿茲海默症潛伏期的人睡眠效率為80.4%,其餘人較好,為83.7%;雖然他們躺在床上的時間相同,但前者真正睡眠的時間較少,打瞌睡的次數也較多。

研究的資深主筆 David M. Holtzman 醫師說,這種關連性提供了一種簡單偵測阿茲海默症的病理學基礎,同時,可以用這項指標來判斷針對帶有阿茲海默症跡象的病患,施以改變睡眠狀況的治療是否成功。

首席主筆人 Yo-El Ju 醫師說,效率低於75%的人,罹患阿茲海默症的機率比正常睡眠者高出五倍。她們將繼續驗證先前那些研究的一個有點嚇人的假設是否為真:睡眠不足與腦中斑塊堆積的關連是雙向的:斑塊堆積會影響睡眠,睡眠不足會助長堆積。

Warsaw_sleeping_men
▲華沙睡覺的男人。(圖片來源: Wikimedia Commons)

(封面圖片來源: Wikimedia Commons)

相關資料
Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway
Why Not Everyone Gets Alzheimer’s
GWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer’s Disease
Genetic markers ID second Alzheimer’s pathway
Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease.
New Alzheimer’s research suggests possible cause: the interaction of proteins in the brain
Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology
New Findings on the Brain’s Immune Cells during Alzheimer’s Disease Progression
Sleep Quality and Preclinical Alzheimer Disease
Sleep loss precedes Alzheimer’s symptoms
阿茲海默症

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