The effects of alpha-secretase ADAM10 on the proteolysis of neuregulin-1.
Although ADAM10 is a major alpha-secretase involved in non-amyloidogenic processing of the amyloid precursor protein, several additional substrates have been identified, most of them in vitro. Thus, therapeutical approaches for the prevention of Alzheimer's disease by upregulation of this metalloproteinase may have severe side effects. In the present study, we examined whether the ErbB receptor ligand neuregulin-1, which is essential for myelination and other important neuronal functions, is cleaved by ADAM10. Studies with beta- and gamma-secretase inhibitors, as well as with the metalloproteinase inhibitor GM6001, revealed an inhibition of neuregulin-1 processing in human astroglioma cell line U373; however, specific RNA interference-induced knockdown of ADAM10 remained without effect. In vivo investigations of mice overexpressing either ADAM10 or dominant negative ADAM10 showed unaltered cleavage of neuregulin-1 compared to wild-type animals. As a consequence, the myelin sheath thickness of peripheral nerves was unaffected in mice with altered ADAM10 activity. Thus, although the beta-secretase BACE-1 acts as a neuregulin-1 sheddase, ADAM10 does not lead to altered neuregulin-1 processing either in cell culture or in vivo. Adverse reactions of an ADAM10-based therapy of Alzheimer's disease due to neuregulin-1 cleavage are therefore unlikely.
Freese
Christian
C
Institute of Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
Garratt
Alistair N
AN
Fahrenholz
Falk
F
Endres
Kristina
K
D051722:ADAM Proteins / Q000502:physiology*; D000072197:ADAM10 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D000818:Animals; D001254:Astrocytoma; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D008565:Membrane Proteins; D020890:Neuregulin-1; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse