Nr CAM is a marker for substrate‐selective activation of ADAM 10 in Alzheimer's disease

Abstract

The metalloprotease ADAM 10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein ( APP ) and lowers amyloid‐beta. Yet, ADAM 10 has additional substrates, which may cause mechanism‐based side effects upon therapeutic ADAM 10 activation. However, they may also serve—in addition to APP —as biomarkers to monitor ADAM 10 activity in patients and to develop APP ‐selective ADAM 10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein Nr CAM . ADAM 10 controlled Nr CAM surface levels and regulated neurite outgrowth in vitro in an Nr CAM ‐dependent manner. However, ADAM 10 cleavage of Nr CAM , in contrast to APP , was not stimulated by the ADAM 10 activator acitretin, suggesting that substrate‐selective ADAM 10 activation may be feasible. Indeed, a whole proteome analysis of human CSF from a phase II clinical trial showed that acitretin, which enhanced APP cleavage by ADAM 10, spared most other ADAM 10 substrates in brain, including Nr CAM . Taken together, this study demonstrates an Nr CAM ‐dependent function for ADAM 10 in neurite outgrowth and reveals that a substrate‐selective, therapeutic ADAM 10 activation is possible and may be monitored with Nr CAM .

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

“…After biosynthesis, the GPI‐anchored protein α2δ undergoes proteolytic maturation, where an as yet unknown protease cleaves within the ectodomain of α2δ, yielding the α2 and the δ subunit which remain linked as a heterodimer through disulfide bridges . Similar proteolytic heterodimer formations with or without disulfide bridges are known for other membrane proteins, such as Notch, NrCAM, and the insulin receptor . While evidence for proteolytic processing of CACHD1 was not reported in the two recent functional studies, our study demonstrates CACHD1 cleavage by BACE1.…”

Tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

“…Thus, Tspan15 and ADAM10 appear to be each required for the normal expression of the other. Indeed, it is well established that TspanC8s are important for ADAM10 maturation and trafficking to the cell surface (Dornier et al 2012; Haining et al 2012; Prox et al 2012; Zhou et al 2014; Jouannet et al 2016; Noy et al 2016; Virreira Winter et al 2016; Reyat et al 2017; Brummer et al 2018; Seipold et al 2018; Shah et al 2018; Brummer et al 2019), and we extended these observations by showing that ADAM10 surface expression was partially reduced in the absence of Tspan15 in A549, HEK-293T and HUVECs. Expression of other TspanC8s by these cells (Haining et al 2012; Matthews et al 2017) is likely to be the reason that the reduction is only partial.…”

“…The TspanC8s comprise Tspan5, 10, 14, 15, 17 and 33, and are so-called because of eight cysteines within their large extracellular loop. Different cell types express distinct TspanC8 repertoires (Matthews et al 2017; Matthews et al 2018) and emerging evidence suggests that each TspanC8 may cause ADAM10 to cleave specific substrates (Dornier et al 2012; Jouannet et al 2016; Noy et al 2016; Reyat et al 2017; Saint-Pol et al 2017; Seipold et al 2018; Brummer et al 2019). However, there is an urgent need to generate monoclonal antibodies (mAbs) to all TspanC8s, to define fully their expression profiles and functional mechanisms.…”

The transcriptomic profiling of COVID-19 compared to SARS, MERS, Ebola, and H1N1

“…Most of these genes are linked to the viral infection immune response of the host, except for genes such as FGF1 and NRCAM. The Neuronal Cell Adhesion Molecule (NRCAM) is related to neurological diseases such as Alzheimer (Brummer et al 2019). Significant NRCAM gene expression has been observed under specific circumstances, such as neuroinflammation triggered by influenza A long-term viral infection (Hosseini et al 2018).…”