♦ See referenced article, J. Biol. Chem. 2011, 286, 37446–37457
Alzheimer disease is characterized by the deposition of β-amyloid plaques in the brain. These plaques are composed of amyloid-β (Aβ) peptide fragments derived from proteolytic cleavage of the amyloid precursor protein (APP). In their Paper of the Week, Kilger et al. demonstrate that the transmembrane British precursor protein BRI2 reduces the accumulation of Aβ fragments by inducing increased expression of the insulin-degrading enzyme (IDE). By crossing a mouse strain overexpressing BRI2 with a mouse model of β-amyloid deposition, the authors found that wild-type BRI2 protein was able to reduce plaque load. In analyzing the plaques, the authors observed that the amount of secreted Aβ was decreased upon overexpression of BRI2. Turning to cell culture, the group investigated the proteases known to degrade Aβ and found that only IDE had a changed expression level upon BRI2 overexpression, with the concentration of its soluble form increasing significantly. To confirm the involvement of secreted IDE in reducing Aβ deposition, the authors added insulin as a competitive inhibitor substrate for IDE and found that reduction of Aβ levels was prevented. Further confirmation was provided by transferring conditioned medium from cells overexpressing BRI2 to cells expressing APP, which showed reduced Aβ deposition relative to untreated cells. The authors then immunodepleted soluble IDE from the conditioned medium and repeated the same experiment. Reduction of Aβ was again prevented, confirming the role of secreted IDE. The authors suggest several possible mechanisms for how BRI2 may cause changes in IDE expression and discuss the potential clinical treatment strategies to which their results point.
BRI2 reduces amyloid plaque deposition in the APPPS1 mouse model of Alzheimer disease.