Amyloid precursor protein (APP) can be cleaved by β-secretase and γ-secretase proteases to generate amyloid-β protein, the main component of senile plaques in Alzheimer's disease, or can be cleaved by α-secretase proteases, precluding the production of amyloid-β protein and generating a secreted, non-amyloidogenic product. Rudolph Tanzi and colleagues previously identified mutations in the ADAM10 gene, which encodes the major α-secretase responsible for cleaving APP, in families with late-onset Alzheimer's disease. Now, they have generated transgenic mice expressing two human ADAM10 mutations in brain, and they report that these mutations increase amyloid-β plaque load (Neuron 80, 385–401, 2013). The authors first showed that the mutant ADAM10 proteins had diminished α-secretase activity on endogenous APP. They then crossed the ADAM10 transgenic lines with a transgenic mouse line that overexpresses human APP and showed that expression of the ADAM10 mutants increased amyloid-β levels in the brain compared to in mice expressing comparable levels of wild-type ADAM10. The authors also used these mouse crosses to show that increasing the level of ADAM10 α-secretase activity in the brain reduced amyloid-β plaque load, plaque morphology and reactive gliosis in the brain. Finally, the authors showed that the ADAM10 alterations, which are located in the prodomain region of the protein, impair the prodomain's chaperone function.