Abstract
The extracellular matrix (ECM) and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A growing body of evidence underscores the multifaceted role of members of the metzincin superfamily, including metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs), A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs) and astacins in physiological and pathological processes in the central nervous system (CNS). The expression and activity of metzincins are strictly controlled at different levels (e.g., through the regulation of translation, limited activation in the extracellular space, the binding of endogenous inhibitors and interactions with other proteins). Thus, unsurprising is that the dysregulation of proteolytic activity, especially the greater expression and activation of metzincins, is associated with neurodegenerative disorders that are considered synaptopathies, especially Alzheimer’s disease (AD). We review current knowledge of the functions of metzincins in the development of AD, mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid β (Aβ) peptide and several pathways for Aβ clearance across brain barriers (i.e., blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB)) that contain specific receptors that mediate the uptake of Aβ peptide. Controlling the proteolytic activity of metzincins in Aβ-induced pathological changes in AD patients’ brains may be a promising therapeutic strategy.
Highlights
Specific proteolysis of the extracellular matrix (ECM) and membrane proteins in close proximity to the synapse emerged as an important mechanism of synaptic plasticity, learning and memory
We review current knowledge of the functions of metzincins in the development of Alzheimer’s disease (AD), mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid β (Aβ) peptide and several pathways for Aβ clearance across brain barriers (i.e., blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB)) that contain specific receptors
Among more than 500 proteases that are encoded in the mammalian genomes (Puente et al, 2003), numerous members of the metzincin superfamily, including metalloproteinases (MMPs), A Disintegrin And Metalloproteinases (ADAMs), A Disintegrin And MMPs with Thrombospondin Motifs (ADAMTSs), and astacins, are implicated in the regulation of various aspects of plasticity in diverse neurons and synapses (Bajor and Kaczmarek, 2013)
Summary
Specific proteolysis of the extracellular matrix (ECM) and membrane proteins in close proximity to the synapse emerged as an important mechanism of synaptic plasticity, learning and memory. The extracellular matrix (ECM) and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A detailed understanding of the mechanisms that regulate the expression and activity of different membrane and extracellular proteases and their substrates at synapses is needed to fully understand the pathological mechanisms that underlie synaptic dysfunctions that are related to such neurodegenerative disorders.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
