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JAMA:删除载脂蛋白E 逆转阿尔茨海默氏症

来源:生物谷 2014-08-14 17:32

2014年8月14日讯 /生物谷BIOON/--虽然载脂蛋白E(ApoE)的突变形式是阿尔茨海默氏症的危险因素,但目前还不知道在一般情况下,载脂蛋白E是否对大脑健康非常重要。因此,还不知道是否完全废除各种形式的载脂蛋白E将是安全的。虽然许多人可能已经按捺不住,以某种方式清除中枢神经系统的载脂蛋白E,但实际结果却不尽如人意。

最近由于一个不寻常的机会,载脂蛋白E在大脑健康中作用的相关问题再次被提出,一名40岁的加州男子患有一种罕见形式的严重脂蛋白血症,他完全没有载脂蛋白E,但认知功能表现正常。

由于载脂蛋白E存在于中枢神经系统和眼视网膜色素上皮细胞中,研究人员Malloy博士研究小组仔细检查该男子的视网膜和神经认知功能。此外,对患者的DNA进行全基因组测序,结果表明该患者携带了某种突变导致载脂蛋白E缺乏症。

研究结果发表在8月11日的JAMA杂志上。尽管完全没有apoE,但他有正常的视力,表现出正常的认知功能、神经系统和视网膜功能,脑部磁共振成像也显示正常的结果,并且脑脊液中β-淀粉样蛋白和tau蛋白处于正常水平。

详细的神经认知研究和视网膜研究,未能证明该患者有缺陷,表明apoE在脑和眼功能中不是关键的,或者它们的功能可能被别的蛋白所替代。令人惊讶的是,对于该患者中枢神经系统功能,似乎没有载脂蛋白E比有apoE4更好。

研究的结论是:靶向敲除降低中枢神经系统的载脂蛋白E,可能是神经变性疾病的新治疗方式。(生物谷Bioon.com)

Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function.

Mak AC1, et al.

IMPORTANCE:
The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).
OBJECTIVES:
To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.
DESIGN, SETTING, AND PARTICIPANTS:
Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.
MAIN OUTCOME MEASURES:
Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.
RESULTS:
The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.
CONCLUSIONS AND RELEVANCE:
Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

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