Jadhav Deepak, Knapinska Anna M, Wang Hongjie, Fields Gregg B
Institute for Human Health & Disease Intervention (I-HEALTH) and Department of Chemistry & Biochemistry, Florida Atlantic University, Jupiter, FL 33458, USA.
Biomolecules. 2025 Aug 3;15(8):1114. doi: 10.3390/biom15081114.
The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer's disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer's disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to endosomal/lysosomal compartments and enhance proinflammatory responses. Overall, the substrate profile of MT5-MMP has not been well defined, and selective inhibitors of MT5-MMP have not been described. These advances will be needed for further consideration of MT5-MMP as a therapeutic target in Alzheimer's disease and other pathologies.
基质金属蛋白酶（MMP）家族包括几种膜结合酶。膜型5基质金属蛋白酶（MT5-MMP）在MMP家族中独一无二，主要在大脑中以及发育过程中表达。有人提出它有助于突触可塑性，并与多种疾病有关，包括多种癌症和阿尔茨海默病。在癌症中，MT5-MMP的表达与癌症进展相关，但尚未发现其独特的机制作用。在阿尔茨海默病中，MT5-MMP表现出促淀粉样蛋白生成活性，作为一种η-分泌酶切割淀粉样前体蛋白（APP），最终产生两个具有突触毒性的片段，Aη-α和Aη-β。已经确定了几种MT5-MMP的细胞内结合伴侣，其中，N4BP2L1、EIG121、BIN1或TMX3与MT5-MMP结合会导致MT5-MMP的η-分泌酶活性显著增加。除了对APP有直接影响外，MT5-MMP还可能促进APP向内体/溶酶体区室的转运，并增强促炎反应。总体而言，MT5-MMP的底物谱尚未明确界定，也未描述MT5-MMP的选择性抑制剂。要进一步将MT5-MMP视为阿尔茨海默病和其他疾病的治疗靶点，还需要这些方面的进展。
