Depletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity

Giuseppina Tesco, Young Ho Koh, Eugene L. Kang, Andrew N. Cameron, Shinjita Das, Miguel Sena-Esteves, Mikko Hiltunen, Shao Hua Yang, Zhenyu Zhong, Yong Shen, James W. Simpkins, Rudolph E. Tanzi

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283 Scopus citations

Abstract

β-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Aβ protein. BACE levels are elevated in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated following cerebral ischemia. However, the molecular mechanism responsible is unknown. We show that increases in BACE and β-secretase activity are due to posttranslational stabilization following caspase activation. We also found that during cerebral ischemia, levels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are increased. RNAi silencing of GGA3 also elevated levels of BACE and Aβ. Finally, in AD brain samples, GGA3 protein levels were significantly decreased and inversely correlated with increased levels of BACE. In summary, we have elucidated a GGA3-dependent mechanism regulating BACE levels and β-secretase activity. This mechanism may explain increased cerebral levels of BACE and Aβ following cerebral ischemia and existing in AD.

Original languageEnglish
Pages (from-to)721-737
Number of pages17
JournalNeuron
Volume54
Issue number5
DOIs
StatePublished - 7 Jun 2007

Keywords

  • CELLBIO
  • HUMDISEASE
  • MOLNEURO

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    Tesco, G., Koh, Y. H., Kang, E. L., Cameron, A. N., Das, S., Sena-Esteves, M., Hiltunen, M., Yang, S. H., Zhong, Z., Shen, Y., Simpkins, J. W., & Tanzi, R. E. (2007). Depletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity. Neuron, 54(5), 721-737. https://doi.org/10.1016/j.neuron.2007.05.012