MT5 MMP- mediated changes in synaptic density, neuronal activity and trafficking of APP b-CTF.
Abstract
Membrane-type 5-matrix metalloproteinase (MT5-MMP) predominantly expressed in neural cells is recently reported to be involved in the proteolytic processing of Amyloid Precursor Protein (APP). The b-C-terminal fragment (b-CTF/C99) generated by cleavage of APP by b-secretase, is the precursor for generation of amyloid beta monomers. The C99 peptide accumulates early in the brains of AD 3xTg and 5xFAD mouse models, even before Aβ and hence plays a major role in the pathology of Alzheimer’s disease. We studied the effect of MT5 domain variants on the levels of C99 as well as its intracellular trafficking in murine primary neuronal cells by over-expressing these via AAV-mediated transduction. The MT5 variants in presence of C99 also impact the synaptic density and neuronal activity suggesting a putative role in the physiology of the neurons.
