More glucose, I mean, more food for thought. The role of insulin in the brain is still emerging and this interesting paper by Gasparini and colleagues presents a novel mechanism by which insulin affects the trafficking of A-beta. They find that insulin, through a tyrosine kinase/MAP kinase kinase pathway, accelerates the APP and A-beta trafficking from the trans-Golgi network to the plasma membrane, but not by generating more A-beta through APP cleavage. This data suggests that alterations of insulin signaling can influence A-beta distribution, which may turn out to be very interesting based on the observations that insulin and A-beta are competing for similar receptors and degrading enzymes. In addition to this novel role, they add to the AD controversy concerning how brain cells might be injured by A-beta by suggesting that a decrease in insulin signaling may enhance the intracellular accumulation of A-beta, which may occur in the AD or aging brain. Even though there is no direct evidence showing intrace.

View all comments by Dean Hartley

We appreciate the analysis/comments of our paper by Dean Hartley, but want to stress that this paper is on the effect of insulin on Aß trafficking/degradation and signal transduction regulation thereof, and does not directly assess the role of intracellular versus extracellular Aß toxicity in AD pathogenesis. Aß toxicity via intracellular and/or extracellular Aß protofibrils was beyond the scope of this paper. We regret not to have cited the very interesting work from his group on Aß protofibrils (among the 55 references we cited). We completely agree with Dean Hartley that the potential role of intraneuronal Aß accumulation in AD pathogenesis is intriguing and requires further investigation. - comments by Gunnar Gouras and Huaxi Xu

View all comments by Gunnar K. Gouras

"This presents a crucial result on the localization and function for BACE but the question remains open whether all of APP is not digested by BACE in distal Golgi membrane, ER, endosome or plasma membrane."

View all comments by Hiroshi Mori