Title:The MMP-2/TIMP-2 System in Alzheimer Disease
Volume: 19
Issue: 6
Author(s): Hongyue Wang, Longjian Huang, Lei Wu, Jiaqi Lan, Xinhong Feng, Pingping Li*Ying Peng*
Affiliation:
- China National Center for Biotechnology Development, Beijing 100039,China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050,China
Keywords:
Matrix metalloproteinase-2, tissue inhibitor of metalloproteinases-2, Alzheimer disease, blood-brain barrier, neuroinflammation,
oxidative stress.
Abstract: Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the
AD brain include Amyloid β-protein (Aβ) plaques and Neurofibrillary Tangles (NFTs), as well as extensive
neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent
protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and
its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review,
we discussed the contributions of dysregulated MMP-2 activity and an imbalanced interaction between
MMP-2 and its endogenous inhibitor, Tissue Inhibitors of Metalloproteinase-2 (TIMP-2), to AD. We
also described the underlying mechanisms of the effects of MMP-2/TIMP-2, both beneficial and detrimental,
on AD, including: (1) MMP-2 directly degrades Aβ resulting in the clearance of Aβ deposits.
Conversely, Aβ-induced MMP-2 may contribute to brain parenchymal destruction. (2) MMP-2 induces
breakdown of BBB, and this deleterious effect could be reversed by TIMP-2. (3) MMP-2 disrupts
oxidative homeostasis in AD. (4) MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/
anti-angiogenetic effects on AD. Besides, we discuss the clinical utility of MMP-
2/TIMP-2 as therapeutic targets for AD.