Sowing the Seeds of Discovery: Tau-Propagation Models of Alzheimer's Disease.
Sowing the Seeds of Discovery: Tau-Propagation Models of Alzheimer's Disease.
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播下发现的种子：阿尔茨海默病的tau繁殖模型。
DOI：
10.1021/acschemneuro.0c00531
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发表时间：
2020-11-04
影响因子：
5
通讯作者：
Slusher BS
中科院分区：
文献类型：
--
作者：
Bell BJ;Malvankar MM;Tallon C;Slusher BS
病理蛋白在整个大脑中的传播是阿尔茨海默病(AD)进展的主要生理标志。越来越多的证据表明，过度磷酸化的Tau蛋白以类似于Prion的方式在神经元之间跨细胞扩散，导致错误折叠和聚集成神经原纤维缠结，并沿着特定的连接路径积累。早期的转基因啮齿动物AD模型未能捕捉到这种与疾病相关的传播，因此，种子Tau繁殖模型已经被开发出来。在这里，突变的人Tau(作为分离蛋白或包装成腺相关病毒(AAV)病毒载体)被立体定向注射到选定的大脑区域，并从组织病理角度对其向下游神经元的传播进行量化。这些模型提供了一种更快速、更直接的机制来评估抑制Tau体内扩散的遗传成分和治疗方法。最近，这些Tau种子模型揭示了AD药物发现的几个新靶点，包括nSMase2、SIRT1、p300/CBP、LRP1和TYROBP，以及基于褪黑素和软骨素酶ABC的潜在治疗方法。重要的是，这些Tau繁殖的啮齿动物模型更接近于人类AD的进展，因此可能会改进临床前研究，并降低未来进入临床试验的风险。
The propagation of pathological proteins throughout the brain is the primary physiological hallmark of the progression of Alzheimer’s Disease (AD). A growing body of evidence indicates that hyperphosphorylated Tau proteins are spread transcellularly between neurons in a prionlike fashion, inducing misfolding and aggregation into neurofibrillary tangles which accumulate along specific connectivity pathways. Earlier transgenic rodent AD models did not capture this disease-relevant spread, and therefore, seeded Tau-propagation models have been developed. Here, mutant human Tau (as isolated protein or packaged into an adeno-associated virus (AAV) viral vector) is stereotaxically injected into select brain regions and its histopathological propagation to downstream neurons quantified. These models offer a faster and more direct mechanism to evaluate genetic components and therapeutic approaches which attenuate Tau spreading in vivo. Recently, these Tau-seeding models have revealed several new targets for AD drug discovery, including nSMase2, SIRT1, p300/CBP, LRP1, and TYROBP, as well as the potential therapeutics based on melatonin and chondroitinase ABC. Importantly, these Tau-propagation rodent models more closely phenocopy the progression of AD in humans and are therefore likely to improve preclinical studies and derisk future moves into clinical trials.
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DOI：
10.1074/jbc.m114.589309
发表时间：
2015-01-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
通讯作者：
Bose S
影响因子：
4.2
作者：
Dinkins MB;Dasgupta S;Wang G;Zhu G;Bieberich E
通讯作者：
Bieberich E
影响因子：
4
作者：
Baker, Sian;Polanco, Juan Carlos;Gotz, Jurgen
通讯作者：
Gotz, Jurgen
影响因子：
14.5
作者：
d'Orange, Marie;Auregan, Gwenaelle;Cambon, Karine
通讯作者：
Cambon, Karine
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K