阿爾茨海默癥是世界上最常見的癡呆病因，人們目前還無法根治這一疾病。阿爾茨海默癥的主要特征之一，是患者大腦產(chǎn)生毒性分子β淀粉樣蛋白。神經(jīng)系統(tǒng)的防御者小膠質(zhì)細胞（Microglial cell）無法清除這一物質(zhì)，導致β淀粉樣蛋白沉積形成老年斑senile plaque，繼而引發(fā)其他相關(guān)病理學癥狀。因此，能夠刺激免疫系統(tǒng)有效清除β淀粉樣蛋白的化合物就具有極大的治療潛力。

Laval大學Serge Rivest教授領(lǐng)導的研究團隊就發(fā)現(xiàn)了這樣一個刺激大腦免疫細胞活性的分子，MPL（單磷酰脂A）。單磷酰脂A是一個LPS衍生的Toll樣受體4激活劑，有獨特的免疫調(diào)節(jié)作用，已經(jīng)被GSK作為疫苗佐劑廣泛使用了多年，其安全性久經(jīng)考驗。

研究人員在十二周內(nèi)給具有阿爾茨海默癥癥狀的小鼠進行每周MPL注射，成功清除了80%的老年斑。他們通過實驗來衡量小鼠學習新任務的能力，發(fā)現(xiàn)在治療過程中小鼠的認知功能得到了顯著提升。

研究人員認為MPL具有兩種應用潛力?？梢杂眠@種藥物對阿爾茨海默癥患者進行肌肉注射，以延緩疾病進程。也可以將其整合到疫苗中去，刺激機體產(chǎn)生針對β淀粉樣蛋白的抗體。“已經(jīng)患有阿爾茨海默癥的患者可以用這種疫苗來刺激自身的天然免疫，” Serge Rivest說。“而那些具有阿爾茨海默癥風險因子的人也可以將這種疫苗作為預防措施。”

這項研究顯示，系統(tǒng)性的重復注射MPL能夠顯著減少小鼠大腦中的β淀粉樣蛋白，大大增強小鼠的認知功能。MPL在觸發(fā)溫和炎癥反應的同時，能誘導小神經(jīng)膠質(zhì)細胞的吞噬作用。

“當我們十年前開始研究阿爾茨海默癥時，我們的目標是為患者開發(fā)更好的治療手段，” Rivest教授說。“這項發(fā)現(xiàn)讓我相信，我們已經(jīng)離這一目標很近了。”

Jean-Philippe Michauda, Maxime Halléb, Antoine Lamprona, Peter Thériaulta, Paul Préfontainea, Mohammed Filalia, Pascale Tribout-Joverb, Anne-Marie Lanteigneb, Rachel Jodoinb, Christopher Cluffc, Vincent Brichardd, Rémi Palmantierd, Anthony Pilorgetb, Daniel Larocqueb,1, and Serge Rivesta,1

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid β (Aβ) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aβ accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aβ may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APPswe/PS1 mice. MPL treatment led to a significant reduction in Aβ load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.