0000000000003883
AUTHOR
Sven Lammich
P3‐335: Upstream of N‐ras (UNR) is involved in translational control of ADAM10 protein expression
Background: The amyloid beta peptide (A ) is derived by proteolytic processing of the amyloid precursor protein (APP) by the beta-secretase BACE1 and gamma-secretase. In contrast to this amyloidogenic processing, APP is predominantly cleaved by the alpha-secretase within the A domain and this precludes the formation of A . We and other research groups could show that BACE1 protein expression is regulated by the 5’untranslated region (UTR) of the BACE1 mRNA, however little is known about the regulation of alpha-secretase. Similar to the 5’UTR of BACE1, the 5’UTR of ADAM10 consists of 444 nucleotides with a GC-content of 70% and two upstream open reading frames. We hypothesize that ADAM10, th…
Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease
Amyloid β peptide (Aβ), the principal proteinaceous component of amyloid plaques in brains of Alzheimer’s disease patients, is derived by proteolytic cleavage of the amyloid precursor protein (APP). Proteolytic cleavage of APP by a putative α-secretase within the Aβ sequence precludes the formation of the amyloidogenic peptides and leads to the release of soluble APPsα into the medium. By overexpression ofa disintegrinandmetalloprotease (ADAM), classified as ADAM 10, in HEK 293 cells, basal and protein kinase C-stimulated α-secretase activity was increased severalfold. The proteolytically activated form of ADAM 10 was localized by cell surface biotinylation in the plasma membrane, but the m…
α-Secretase Activity of the Disintegrin Metalloprotease ADAM 10: Influences of Domain Structure
Disintegrin metalloproteases from different organisms form the ADAM (a disintegrin and metalloprotease) family. All members display a common domain organization and possess four potential functions: proteolysis, cell adhesion, cell fusion, and cell signaling. Members of the ADAM family are responsible for the proteolytic cleavage of transmembrane proteins and release of their extracellular domain. The proteolytic process is referred to as ectodomain shedding, which is activated by phorbol esters and inhibited by hydroxamic acid-based inhibitors. We have shown that the disintegrin metalloprotease ADAM 10 has both constitutive and regulated alpha-secretase activity. Expression of a dominant n…
Expression of the Anti-amyloidogenic Secretase ADAM10 Is Suppressed by Its 5′-Untranslated Region*
Proteolytic processing of the amyloid precursor protein by alpha-secretase prevents formation of the amyloid beta-peptide (Abeta), which is the main constituent of amyloid plaques in brains of Alzheimer disease (AD) patients. alpha-Secretase activity is decreased in AD, and overexpression of the alpha-secretase ADAM10 (a disintegrin and metalloprotease 10) in an AD animal model prevents amyloid pathology. ADAM10 has a 444-nucleotide-long, very GC-rich 5'-untranslated region (5'-UTR) with two upstream open reading frames. Because similar properties of 5'-UTRs are found in transcripts of many genes, which are regulated by translational control mechanisms, we asked whether ADAM10 expression is…
Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10
Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the α-secretase ADAM 10 ( a d isintegrin a nd m etalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-β-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted α-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increa…