Neuronal activity and secreted amyloid ? lead to altered amyloid ? precursor protein and presenilin 1 interactions.

ABSTRACT: Deposition of amyloid ? (A?) containing plaques in the brain is one of the neuropathological hallmarks of Alzheimer's disease (AD). It has been suggested that modulation of neuronal activity may alter A? production in the brain. We postulate that these changes in A? production are due to changes in the rate-limiting step of A? generation, APP cleavage by ?-secretase. By combining biochemical approaches with fluorescence lifetime imaging microscopy, we found that neuronal inhibition decreases endogenous APP and PS1 interactions, which correlates with reduced A? production. By contrast, neuronal activation had a two-phase effect: it initially enhanced APP-PS1 interaction leading to increased A? production, which followed by a decrease in the APP and PS1 proximity/interaction. Accordingly, treatment of neurons with naturally secreted A? isolated from AD brain or with synthetic A? resulted in reduced APP and PS1 proximity. Moreover, applying low concentration of A?(42) to cultured neurons inhibited de novo A? synthesis. These data provide evidence that neuronal activity regulates endogenous APP-PS1 interactions, and suggest a model of a product-enzyme negative feedback. Thus, under normal physiological conditions A? may impact its own production by modifying ?-secretase cleavage of APP. Disruption of this negative modulation may cause A? overproduction leading to neurotoxicity.

SUBMITTER: Li X 

PROVIDER: S-EPMC3534898 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature