| First Author | Li X | Year | 2013 |
| Journal | Neurobiol Dis | Volume | 50 |
| Pages | 127-34 | PubMed ID | 23064434 |
| Mgi Jnum | J:197499 | Mgi Id | MGI:5493197 |
| Doi | 10.1016/j.nbd.2012.10.002 | Citation | Li X, et al. (2013) Neuronal activity and secreted amyloid beta lead to altered amyloid beta precursor protein and presenilin 1 interactions. Neurobiol Dis 50:127-34 |
| abstractText | Deposition of amyloid beta (Abeta) 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 Abeta production in the brain. We postulate that these changes in Abeta production are due to changes in the rate-limiting step of Abeta generation, APP cleavage by gamma-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 Abeta production. By contrast, neuronal activation had a two-phase effect: it initially enhanced APP-PS1 interaction leading to increased Abeta production, which followed by a decrease in the APP and PS1 proximity/interaction. Accordingly, treatment of neurons with naturally secreted Abeta isolated from AD brain or with synthetic Abeta resulted in reduced APP and PS1 proximity. Moreover, applying low concentration of Abeta(42) to cultured neurons inhibited de novo Abeta 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 Abeta may impact its own production by modifying gamma-secretase cleavage of APP. Disruption of this negative modulation may cause Abeta overproduction leading to neurotoxicity. |
