Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking.

MT1-MMP upregulation in 5xFAD mice timely and spatially correlates with the increase in C99 levels, providing indirect in vivo support for the pro-amyloidogenic features of this MMP described in HEKswe cells.

“MT1-MMP upregulation in 5xFAD mice timely and spatially correlates with the increase in C99 levels (Py et al., 2014), thus providing indirect in vivo support for the pro-amyloidogenic features of this MMP described in HEKswe cells (Paumier et al., 2019).”

About 50% of the sAPP95 released after MT1-MMP expression in HEKswe cells results from concerted action with MMP-2, MT1-MMP being the limiting factor in this enzymatic tandem.

“It is estimated that about 50% of the sAPP95 released after MT1-MMP expression in HEKswe cells results from concerted action with MMP-2, MT1-MMP being in any case the limiting factor in this enzymatic tandem (Paumier et al., 2019).”

MT1-MMP can prominently increase Aβ levels in the HEK293 cell model of amyloidogenesis stably expressing APP with the familial Swedish mutation (HEKswe).

“In complement of these results, we have recently reported that MT1-MMP can also prominently increase Aβ levels in the HEK293 cell model of amyloidogenesis, which stably expresses APP with the familial Swedish mutation (HEKswe) (Paumier et al., 2019).”

MT1-MMP could function as a surrogate β-secretase when BACE-1 is inhibited; this is supported by experiments in HEKswe cells where MT1-MMP restores basal levels of Aβ almost abolished by BACE-1 inhibitor IV (or C3).

“Most interestingly, it has been proposed that MT1-MMP could also function as a surrogate β-secretase when BACE-1 is inhibited; this is supported by experiments in HEKswe cells where MT1-MMP is able to restore the basal levels of Aβ, almost abolished in the presence of BACE-1 inhibitor IV (or C3) (Paumier et al., 2019).”

MT1-MMP could favor amyloidogenic β-secretase processing by promoting APP sorting into BACE-1-enriched early endosomes.

“Not exclusively, MT1-MMP could favor amyloidogenic β-secretase processing by promoting APP sorting into BACE-1-enriched early endosomes (Paumier et al., 2019).”

The complementary transmembrane fragment of ~30 kDa (CTF-30) and C99 are dramatically increased and their levels highly correlated, suggesting that CTF-30 may be the precursor of C99.

“The complementary transmembrane fragment of ∼30 kDa (CTF-30) and C99 are also dramatically increased and their levels highly correlated, suggesting that CTF-30 may be the precursor of C99 (Paumier et al., 2019).”

For each experiment, cDNA samples were analyzed in duplicate and relative gene expression was obtained using the comparative 2−(ΔΔCt) method after normalization to the Gapdh housekeeping gene.

“For each experiment, cDNA samples were analyzed in duplicate and relative gene expression was obtained using the comparative 2−(ΔΔCt) method after normalization to the Gapdh (Mm99999915_g1) housekeeping gene [32, 33].”

MT1-MMP, MMP-9 and MMP-2 are close MT5-MMP homologues involved in the control of APP metabolism and amyloidogenesis.

“all close MT5-MMP homologues, also involved in the control of APP metabolism and amyloidogenesis [33, 34, 54, 55]”