T he amyloid β-peptide (Aβ peptide) is assumed to play a crucial and early role in the pathogenesis of Alzheimer disease. Thus, strategies for a pharmacotherapy aim at reducing Aβ peptide generation, which proteolytically derives from the amyloid precursor protein (APP). The main targets so far have been β- and γ-secretase, the two proteases that cleave APP at the N- and C-terminus of the Aβ peptide and are thus directly responsible for Aβ peptide generation. A different strategy, namely the activation of α-secretase, has barely been investigated for its therapeutic potential. α-Secretase cleaves within the Aβ peptide domain and thus precludes Aβ peptide generation. Now, new results demonstrate that activation of α-secretase indeed reduces Aβ peptide generation and toxicity in vivo.