Abstract: To define the enzymes involved in the etiology of Alzheimer's disease, we compared in mouse and human brain the mRNA levels and cellular localization of the ubiquitous β‐amyloid precursor protein (β‐APP) with those of the putative α‐secretases ADAM10 and ADAM17 and the β‐secretases BACE and BACE2. In situ hybridization performed in mice during prenatal and postnatal development and in adulthood revealed the coexpression of β‐APP, BACE, and ADAM10. The patterns of BACE2 and ADAM17 only partially overlapped with that of β‐APP. β‐APP, BACE, and ADAM10 mRNAs have also been detected by northern blot in human brain cortex of normal subjects and in Alzheimer's disease subjects. In situ hybridization performed using combined biotin‐ and radiolabeled riboprobes provided evidence for the coexpression of β‐APP with BACE and ADAM10 in human cortical neurons. Our data provide cytochemical evidence supporting the role of ADAM10 and BACE as authentic α‐ and β‐secretases.