Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE.
ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function.
Neuron. 2013 Oct 16;80(2):385-401.
Please login to recommend the paper.
To make a comment you must login or register.
The human ADAM10 mutations Q170H and R181G within the prodomain of the protein have been previously found in several late-onset AD families (Kim et al., 2009). To validate the pathogenicity of the mutations, classical transgenic mice expressing wild type or the LOAD mutations were generated and characterized. It was found that the LOAD mutations attenuate (but do not abolish) ADAM10 alpha-secretase activity, and increase beta-secretase cleavage of APP. Compared to the wild-type situation, the mutants increase Abeta accumulation in AD mouse brains.
The study is based on dominant-negative effect of ADAM10 expression on endogenous ADAM10 in mice, as has been shown earlier by Postina et al. some years ago (Postina et al, 2004). It again confirms the essential role of ADAM10 (and not of any other suspected ADAM protease) for alpha secretase processing of APP. This highlights its role in human AD patients, urging for more intensive screening for additional ADAM10 mutations.
Surprisingly, the dominant-negative effects of the transgenic mutation were apparently only affecting the APP substrate, whereas other neuronal substrates such as N-cadherin or Notch appear to be unaffected by these mutations. Perhaps knockin mice mimicking the human pro domain mutations would have been even more convincing.
The role of ADAM10 in neurogenesis in the hippocampus is interesting but certainly needs additional efforts to understand this at a molecular level. The role of ADAM10 in the adult CNS, including its role in APP processing and endogenous Abeta generation has also been revealed by our group (Prox et al. JN 2013).
In summary, this is an elegant study providing additional and valuable insight into the function of previously described ADAM10 mutations leading to AD.
We would like to address the concern of Drs. Postina and Kojro, who questioned whether increased Aβ levels in the ADAM10 X Tg2576 mouse brains could be due to differences in ADAM10 expression versus effects of the ADAM10 LOAD mutations. We refer to Figure 1, which clearly shows very similar levels of ADAM10 expression among the three lines that were carefully chosen for wild-type and each ADAM10 mutation. In that same figure, auto-proteolysis of ADAM10 to generate the ADAM10-CTF is clearly impaired by both LOAD mutations. This would not be due to differences in expression levels.
In these same lines, one can also observe a shift of APP from α- to β-secretase cleavage for both mutations vs. wild-type, with similar levels of ADAM10 expression (Figures 1 and 2). The observation of this shift in the single ADAM10 transgenics (Figure 1), in the absence of mutant APP, also addresses the question of whether the same profile would appear in those who do not over-express mutant APP?
Finally, we note that the observed moderate (statistically significant) increases in total Aβ (Figure 3) owing to the ADAM10 mutations would be consistent with the average age of onset of 70 years in the seven carrier AD families.