Current Insights on CNS-Targeted Matrix Metalloproteinase Inhibitors for the Management of Alzheimer's Disease

Matrix metalloproteinases, or MMPs, are enzymes that depend on zinc and play a key role in remodelling the extracellular matrix as well as regulating neuroinflammation within the central nervous system. There's growing evidence that when MMP activity is imbalanced, it contributes to the development of Alzheimer's disease. Interestingly, these enzymes are involved in beneficial and harmful processes such as amyloid-β (Aβ) destruction, disrupting the blood-brain barrier, and fuelling neuroinflammation. This review focused on the recent progress made between 2015 and 2025 in understanding the role of MMPs in Alzheimer's disease, especially focusing on their complexity. We also included key studies published before 2015 to give a basic understanding of MMP biology. The search strategy employed a combination of keywords and Boolean operators, including "Alzheimer's disease," "matrix metalloproteinase," and "MMP inhibitor," used both independently and in various combinations to maximize retrieval sensitivity. To gather the information, a thorough search was carried out using the PubMed database, and studies were selected based on relevance, quality of their methods, and potential to be applied in real-world settings. Following this rigorous screening and eligibility assessment process, approximately 85 articles were selected for detailed qualitative analysis. We analyzed the roles of key MMPs, such as MMP-2, MMP-9, MMP-3, and the membrane-type MMPs, with inconsistencies found across different studies to explore possible issues. Additionally, we also provide an overview of the latest progress in developing both natural and synthetic MMP inhibitors, paying special attention to how they work and their potential as therapies. This review highlights some of the key challenges that are retarding clinical progress, such as the lack of target selectivity, unwanted off-target activity, and the difficulty in crossing the blood-brain barrier. We also discussed promising new approaches, including selective inhibition, designing drugs with multiple functions, and advanced methods for delivering treatments to the central nervous system. Overall, MMPs are promising but quite complex targets when it comes to treating Alzheimer's disease. For translational research, it's crucial to gain a deeper understanding of how these enzymes work in different contexts and to develop selective inhibitors that can effectively reach the brain.