美国研究人员在新一期《神经元》(Neuron)杂志上报告说,大脑血糖含量长期缓慢降低,可能诱发早老性痴呆症。
美国西北大学芝加哥芬伯格医学院的罗伯特·瓦萨等人对人类和老鼠大脑研究后发现,大脑血糖含量缓慢降低会导致大脑血流量降低,从而使大脑能量不足。如果这种情况长期出现,会导致一种名叫elF2alpha的蛋白发生变异,从而促成一种特定酶的形成,这种酶能引发导致早老性痴呆症的大脑贝塔淀粉样蛋白堆积。
瓦萨说,这一研究成果有助于开发通过抑制elF2alpha蛋白生成来治疗早老性痴呆症的药物。
早老性痴呆症又称阿尔茨海默氏症,是最常见的老年痴呆症,其临床表现为认知、记忆和语言功能出现障碍等。研究人员认为,人们可以通过加强锻炼、降低胆固醇和控制血压来提高大脑血糖含量水平,从而改善大脑血流状况,预防早老性痴呆症。(生物谷Bioon.com)
生物谷推荐原始出处:
Neuron,Volume 60, Issue 6, 988-1009,Tracy O'Connor,Robert Vassar
Phosphorylation of the Translation Initiation Factor eIF2 Increases BACE1 Levels and Promotes Amyloidogenesis
Tracy O'Connor1,Katherine R. Sadleir1,Erika Maus1,Rodney A. Velliquette1,Jie Zhao1,Sarah L. Cole1,William A. Eimer1,Brian Hitt1,Leslie A. Bembinster1,Sven Lammich2,Stefan F. Lichtenthaler2,Sébastien S. Hébert3,Bart De Strooper3,Christian Haass2,David A. Bennett4andRobert Vassar1,,
1 Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2 Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Center for Integrated Protein Science Munich and Adolf-Butenandt-Institute, Ludwig-Maximilians-University, 80539 Munich, Germany
3 Department of Molecular and Developmental Genetics, VIB, Center for Human Genetics, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
4 Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for β-amyloid (Aβ) production, is elevated in Alzheimer's disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2α (eIF2α-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2α-P phosphatase PP1c, directly increases BACE1 and elevates Aβ production in primary neurons. Preventing eIF2α phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant-negative eIF2α kinase PERK, or PERK inhibitor P58IPK blocks the energy-deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2α-P, BACE1, Aβ, and amyloid plaques. Importantly, eIF2α-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2-αP, and amyloid load are correlated in humans with AD. These results strongly suggest that eIF2 αphosphorylation increases BACE1 levels and causes A βoverproduction, which could be an early, initiating molecular mechanism in sporadic AD.