Molecular Neuroplasticity, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany.
Inst Neurophysiopathol, CNRS, INP, Aix Marseille Université, 13385 Marseille, France.
Cells. 2021 Jul 6;10(7):1705. doi: 10.3390/cells10071705.
For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer's disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target. However, a more comprehensive analysis of the role of MT5-MMP is necessary to evaluate how its targeting affects neurons and glia in pathological and physiological situations. In this study, leveraging on CRISPR-Cas9 genome editing strategy, we established cultures of human-induced pluripotent stem cells (hiPSC)-derived neurons and astrocytes to investigate the impact of MT5-MMP deficiency on their phenotypes. We found that MT5-MMP-deficient neurons exhibited an increased number of primary and secondary neurites, as compared to isogenic hiPSC-derived neurons. Moreover, MT5-MMP-deficient astrocytes displayed higher surface area and volume compared to control astrocytes. The MT5-MMP-deficient astrocytes also exhibited decreased GLAST and S100β expression. These findings provide novel insights into the physiological role of MT5-MMP in human neurons and astrocytes, suggesting that therapeutic strategies targeting MT5-MMP should be controlled for potential side effects on astrocytic physiology and neuronal morphology.
一段时间以来，人们一直认为β-位点 APP 切割酶 1（BACE1）和 γ-分泌酶是β-淀粉样前体蛋白（APP）淀粉样蛋白生成过程中的两个主要参与者。最近，主要在神经系统中表达的膜型 5 基质金属蛋白酶（MT5-MMP/MMP-24）已被强调为 APP 加工的新关键参与者，能够刺激淀粉样蛋白生成，也能产生神经毒性 APP 衍生物。此外，已经证明 MT5-MMP 的缺失可以消除阿尔茨海默病（AD）小鼠模型中的病理特征，从而为 MT5-MMP 作为有吸引力的新治疗靶点提供了依据。然而，需要更全面地分析 MT5-MMP 的作用，以评估靶向 MT5-MMP 如何影响病理和生理情况下的神经元和神经胶质。在这项研究中，我们利用 CRISPR-Cas9 基因组编辑策略，建立了人诱导多能干细胞（hiPSC）衍生神经元和星形胶质细胞的培养物，以研究 MT5-MMP 缺乏对其表型的影响。我们发现，与同基因 hiPSC 衍生神经元相比，MT5-MMP 缺陷神经元的初级和次级神经突数量增加。此外，与对照星形胶质细胞相比，MT5-MMP 缺陷星形胶质细胞的表面积和体积更大。MT5-MMP 缺陷星形胶质细胞的 GLAST 和 S100β 表达也降低。这些发现为 MT5-MMP 在人类神经元和星形胶质细胞中的生理作用提供了新的见解，表明针对 MT5-MMP 的治疗策略应控制其对星形胶质细胞生理和神经元形态的潜在副作用。
