據(jù)3月13日的《科學》雜志報道說,，根據(jù)一項新的研究披露,，對一種造成阿爾茨海默病的基因的變異來說,，如果某人從其雙親那里遺傳了該種變異的基因的話，其罹患阿爾茨海默病的機會比僅從父母中一個人那里遺傳該變異基因的機會要小,。
研究發(fā)現(xiàn),，這種由單個基因變異而產(chǎn)生的保護性作用可能為治療阿爾茨海默病提供新的途徑。 這些發(fā)現(xiàn)還表明有這樣的可能,，即其它的被認為無害的基因變異如果被遺傳了雙份的話就可能會引起疾病,。這進而表明，在一個具有該種疾病歷史的家族中有必要進行遺傳學的篩檢,。 在所有的阿爾茨海默癥病例中,，只有非常小的比例是因為遺傳造成的，但這些病例常常會在生命的相對較早的時期出現(xiàn)并比該病的其它形式會更快地進展,。 現(xiàn)在發(fā)現(xiàn)的是遺傳性阿爾茨海默病的第一個已知的隱性基因變異,；其它類型的已知基因變異都是顯性的,，即只要遺傳有一份這樣基因就足以引起該種疾病。 所有這些變異都發(fā)生在淀粉樣蛋白前體（或稱APP）之中,，該蛋白前體會被多種酶切割成“β-淀粉樣蛋白”片斷,，該蛋白片斷會在阿爾茨海默病患者的腦中積聚。
Giuseppe Di Fede及其在意大利的同僚現(xiàn)在描述了一種叫做A673V的APP變異,，它會導致β-淀粉樣蛋白產(chǎn)生的增加并增加了β-淀粉樣蛋白積聚的可能性,，從而形成淀粉樣的纖維。 但是,，在雜合子患者中,，正常蛋白與變異蛋白之間的相互作用有時會阻斷這一變化，從而在實際上阻止了β-淀粉樣蛋白的產(chǎn)生,。 這一發(fā)現(xiàn)可能可以解釋為什么雜合子基因攜帶者即使在非常老的年齡也不會得該種疾病,。（生物谷Bioon.com）
生物谷推薦原始出處：
Science 13 March 2009:DOI: 10.1126/science.1168979
A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis
Giuseppe Di Fede,1 Marcella Catania,1 Michela Morbin,1 Giacomina Rossi,1 Silvia Suardi,1 Giulia Mazzoleni,1 Marco Merlin,1 Anna Rita Giovagnoli,1 Sara Prioni,1 Alessandra Erbetta,2 Chiara Falcone,3 Marco Gobbi,4 Laura Colombo,4 Antonio Bastone,4 Marten Beeg,4 Claudia Manzoni,4 Bruna Francescucci,5 Alberto Spagnoli,5 Laura Cantù,6 Elena Del Favero,6 Efrat Levy,7 Mario Salmona,4 Fabrizio Tagliavini1*
β-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.
1 Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
2 Division of Neuroradiology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
3 Division of Neuroepidemiology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
4 Department of Molecular Biochemistry and Pharmachology, Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
5 Division of Cognitive Disorders, Centro Sant'Ambrogio Fatebenefratelli, Cernusco sul Naviglio, 20063 Milan, Italy.
6 Department of Medical Chemistry, Biochemistry, and Biotechnology, University of Milan, Segrate, 20090 Milan, Italy.
7 Departments of Pharmacology and Psychiatry, New York University School of Medicine, and Nathan S. Kline Institute, Orangeburg, NY 10962, USA.
