Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease
Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease
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DOI：
10.1080/19336896.2015.1123371
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发表时间：
2016-01-02
期刊：
影响因子：
2.3
通讯作者：
Safar, Jiri G.
中科院分区：
文献类型：
--
作者：
Cohen, Mark;Appleby, Brian;Safar, Jiri G.
关于人类朊病毒的大量证据表明，致病性朊病毒蛋白（PrPSc）的独特构象（菌株）决定了不同的疾病表型、传播速率和不同脑结构的靶向。最近的进展，在先进的生物物理工具，库存的淀粉样蛋白β（A β）在大脑皮层的表型多样性阿尔茨海默氏病（AD）患者的结构特征的发展，揭示了独特的频谱的寡聚颗粒在皮层的快速进展的情况下，牵连这些结构在大脑中的可变速率的传播，并在distict疾病的表现。由于只有大约30%的AD表型多样性可以通过风险基因的多态性来解释，因此这些和转基因生物测定数据认为，结构上不同的A β颗粒在AD的不同发病机制中起主要作用，并且可能表现为编码不同表型的不同朊病毒样菌株。从这些观察和我们对朊病毒的日益了解，迫切需要新的菌株特异性诊断策略，用于错误折叠的蛋白质导致这些难以捉摸的疾病。由于靶向药物治疗可以诱导朊病毒突变和进化成新的菌株，有效的治疗AD将需要药物，提高清除致病构象，减少前体蛋白，或抑制前体转化为朊病毒样状态。
Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrPSc). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (A beta) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only similar to 30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct A beta particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.