Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
ACS Chem Neurosci. 2020 Nov 4;11(21):3499-3509. doi: 10.1021/acschemneuro.0c00531. Epub 2020 Oct 13.
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 . 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.
病理性蛋白质在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 蛋白以类朊病毒的方式在神经元之间进行细胞间传播，诱导错误折叠和聚集形成神经原纤维缠结，沿着特定的连接通路积累。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，已经开发了 Tau 传播模型。在这里，突变型人 Tau（作为分离的蛋白质或包装到腺相关病毒（AAV）病毒载体中）被立体定向注射到选定的脑区，并对其下游神经元的组织病理学传播进行定量。这些模型提供了一种更快、更直接的机制来评估遗传成分和治疗方法，以减轻 Tau 的传播。最近，这些 Tau 播种模型揭示了 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 传播啮齿动物模型更密切地模拟了人类 AD 的进展，因此可能会改善临床前研究，并降低未来进入临床试验的风险。
