Predictive Pharmacology, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.
Centre for Human Drug Research (CHDR), 2333 CL Leiden, The Netherlands.
Int J Mol Sci. 2020 Apr 30;21(9):3158. doi: 10.3390/ijms21093158.
To diagnose and treat early-stage (preclinical) Alzheimer's disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers. In human studies, amyloid beta (Aβ), hyperphosphorylated tau (P-tau), total tau (T-tau), neurogranin, SNAP-25, glial fibrillary acidic protein (GFAP), YKL-40, and especially neurofilament light (NfL) are frequently measured. In animal studies, the emphasis has been mostly on Aβ. Although a direct comparison between human (familial and sporadic) AD and (mostly genetic) animal AD models cannot be made, still, in brain, cerebrospinal fluid (CSF), and blood, a majority of similar trends are observed for human AD stage and animal AD model life stage. This indicates the potential value of animal AD models in understanding of the onset and early stage of AD. Moreover, animal studies can be smartly designed to provide mechanistic information on the interrelationships between the different AD processes in a longitudinal fashion and may also include the combinations of different conditions that may reflect comorbidities in human AD, according to the Mastermind Research approach.
为了诊断和治疗早期（临床前）阿尔茨海默病（AD）患者，我们需要能够反映该阶段发生过程的体液生物标志物，但目前对相关过程的了解还很缺乏。由于对（可能）发病和早期 AD 进行人类研究将极其昂贵和耗时，因此我们研究了动物 AD 模型的潜在价值，以帮助填补这一知识空白。我们全面概述了与 AD 发病机制和生物标志物相关的过程、从人类和动物大脑及体液中获得的与 AD 相关生物标志物的现有知识、在人类 AD 和常用动物 AD 模型中获得的生物标志物的比较，以及新兴的体液生物标志物。在人类研究中，经常测量淀粉样蛋白β（Aβ）、过度磷酸化的 tau（P-tau）、总 tau（T-tau）、神经颗粒蛋白、突触相关蛋白 25（SNAP-25）、神经胶质纤维酸性蛋白（GFAP）、YKL-40，尤其是神经丝轻链（NfL）。在动物研究中，重点主要放在 Aβ 上。尽管不能直接将人类（家族性和散发性）AD 与（主要是遗传性）动物 AD 模型进行比较，但在大脑、脑脊液（CSF）和血液中，仍然观察到人类 AD 阶段和动物 AD 模型生命阶段的大多数类似趋势。这表明动物 AD 模型在理解 AD 的发病和早期阶段具有潜在价值。此外，根据“聪明大脑”研究方法，动物研究可以巧妙地设计，以提供不同 AD 过程之间的纵向相互关系的机制信息，并且还可以包括可能反映人类 AD 合并症的不同条件的组合。
