Cerebral deposition of beta-amyloid peptide (beta A) is a hallmark of Alzheimer's disease. Concentration of beta A could play a critical role in the rate of amyloid deposition. It is therefore of considerable importance to identify proteases involved in processing of beta A. 125I-labeled synthetic beta A specifically cross-linked to a single protein with M(r) = 110,000 in cytosol fractions from rat brain and liver. This protein was identified as insulin degrading enzyme (IDE) since the labeling of the 110 kDa protein was completely blocked by an excess of insulin, and anti-IDE monoclonal antibodies precipitated the labeled protein. Purified rat IDE effectively degraded beta A.