2013年6月18日訊 /生物谷BIOON/--近日，一項新的研究表明,，老年小鼠阿爾茨海默氏癥的病理記憶可以逆轉(zhuǎn)得到恢復(fù)治療,。蒙特利爾神經(jīng)學(xué)研究所、麥吉爾大學(xué)和蒙特利爾大學(xué)的研究人員的研究發(fā)現(xiàn),，阻斷阿爾茨海默氏?。ˋD）小鼠大腦中的一個特定的受體的活性，能恢復(fù)記憶和腦功能,。
研究結(jié)果發(fā)表在Journal of Neuroinflammation雜志上,，新研究揭示了AD的基本機(jī)制，并標(biāo)明該受體可作為一個潛在的新療法靶標(biāo),。
神經(jīng)學(xué)家Edith Hamel說：這項研究是令人興奮的,，因為這種分子甚至對動物晚期病理也效。研究人員發(fā)現(xiàn),，緩激肽B1受體（B1R）在AD小鼠腦組織中水平提高,，該受體參與炎癥反應(yīng)。
分子選擇性地阻止這種受體的作用后，研究人員觀察到認(rèn)知和腦功能得到了改進(jìn),。阿爾茨海默氏病破壞神經(jīng)細(xì)胞,，也有損大腦中的血管功能。大腦血管的正常運作對提供營養(yǎng)和氧氣給神經(jīng)細(xì)胞是非常重要的,，高齡老人的血管疾病是AD的重要危險因素,。
另一個有趣的結(jié)果是小鼠模型中減少超過50％的毒性β-淀粉樣肽，在阿爾茨海默氏病,，蛋白質(zhì)片段β-淀粉樣蛋白對血液和神經(jīng)系統(tǒng)產(chǎn)生有害影響,，通常情況下這些蛋白質(zhì)片段被分解并除去。
在阿爾茨海默氏病,，蛋白質(zhì)片段聚集在一起,，影響神經(jīng)細(xì)胞和血管功能。目前仍不知道如果β-淀粉樣蛋白降低是否有助于功能的恢復(fù),。但結(jié)果顯示,，B1R增加與阿爾茨海默氏病小鼠記憶受損相關(guān)的β-淀粉樣斑塊相關(guān)，慢性封鎖B1R后能顯著提高學(xué)習(xí),，記憶,，腦血管功能和AD其他幾個病理標(biāo)志。
總之,，這些研究結(jié)果揭示了B1R在AD的發(fā)病機(jī)制,，接下來的步驟將考察緩激肽B1R潛在阻滯劑對AD患者的治療作用。（生物谷Bioon.com）
doi:10.1186/1742-2094-10-57
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Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer's disease mice
Baptiste Lacoste, Xin-Kang Tong, Karim Lahjouji, Réjean Couture and Edith Hamel
Background
Recent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Abeta) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B1R on cognitive and cerebrovascular functions in a mouse model of Alzheimer's disease (AD).
Methods
Transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APPSwe,Ind, line J20) were treated with a selective and brain penetrant B1R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B1R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Abeta burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry.
Results
B1R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Abeta plaques. In APP mice, B1R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B1R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B2R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Abeta1-42, diffuse and dense-core Abeta plaques, and it increased protein levels of the Abeta brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels.
Conclusion
These findings show a selective upregulation of astroglial B1R in the APP mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B1R in AD pathogenesis.
