ADAMTS‐4 in oligodendrocytes contributes to myelination with an impact on motor function

Abstract

Myelination is a late developmental process regulated by a set of inhibitory and stimulatory factors, including extracellular matrix components. Accordingly, chondroitin sulfate proteoglycans (CSPGs) act as negative regulators of myelination processes. A disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4) is an extracellular protease capable of degrading CSPGs. Although exogenous ADAMTS-4 has been proven to be beneficial in several models of central nervous system (CNS) injuries, the physiological functions of endogenous ADAMTS-4 remain poorly understood. We first used Adamts4/LacZ reporter mice to reveal that ADAMTS-4 is strongly expressed in the CNS, especially in the white matter, with a cellular profile restricted to mature oligodendrocytes. Interestingly, we evidenced an abnormal myelination in Adamts4 mice, characterized by a higher diameter of myelinated axons with a shifting g-ratio. Accordingly, lack of ADAMTS-4 is accompanied by motor deficits and disturbed nervous electrical activity. In conclusion, we demonstrate that ADAMTS-4 is a new marker of mature oligodendrocytes contributing to the myelination processes and thus to the control of motor capacities.

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

“…In the adult mouse brain, expression of β-galactosidase was exclusively localized to Olig2-positive oligodendrocytes. Further studies demonstrated that ADAMTS4 expression was restricted to cells co-expressing adenomatous-polyposis-coli protein, a marker for mature oligodendrocytes [61]. Finally, the exclusive expression of ADAMTS4 in oligodendrocytes is consistent with our immunohistochemical detection of Aβ4-x peptides in white matter fiber tracts and neuronal processes in cortical areas.…”

“…This was further confirmed in a proteome study of murine brain cell types, in which ADAMTS4 belonged to the 10 most abundant proteins specifically expressed in cultured murine oligodendrocytes [69]. Most importantly, during the preparation of this manuscript, another research group had reported the use of the same ADAMTS4 −/− KO reporter mouse strain to study the expression of ADAMTS4 in the brain, and had also detected ADAMTS4 in oligodendrocytes [61]. In the adult mouse brain, expression of β-galactosidase was exclusively localized to Olig2-positive oligodendrocytes.…”

“…To validate the relevance of ADAMTS4 for Aβ generation and APP processing in vivo, ADAMTS4 −/− knockout (KO) mice were crossed to the 5xFAD model of AD [54,61]. Consistent with previous results [62], mass spectrometry analysis of Aβ peptide species in the brains of 12-month-old Supplementary Fig.…”

“…The remarkable, ADAMTS4-dependent localization of Aβ4-x peptides to white matter fiber tracts and neuronal processes prompted us to investigate the expression of ADAMTS4 in the adult murine brain. Prior studies had provided conflicting results and evidence for ADAMTS4 expression in both neurons and all glial cell types of the central nervous system (CNS) [19,39,43,61,69,82]. We took advantage of the ADAMTS4 −/− KO mice, in which the ADAMTS4 gene locus was disrupted by insertion of a bacterial lacZ gene such that the endogenous ADAMTS4 gene promotor would drive the expression of β-galactosidase (β-gal).…”

Single cell atlas of domestic pig brain illuminates the conservation and divergence of cell types at spatial and species levels

“…Firstly in C0 (OLG), we found ADAMTS4, a protease that controls the degradation of a brain-specific extracellular matrix protein -brevican [102], specifically expressed in mouse cells (Figure 4f). Previously ADAMTS4 has been reported to be a marker of mature oligodendrocytes in mouse brain and may promote the generation of myelin sheath [103]. Additionally, TMEM125 and TSPAN2, both known to contribute to neuron myelination in mouse or rat [104,105], also displayed a similar expression pattern as ADAMTS4 ( Figure S7).…”