Depletion of GGA3 Stabilizes BACE and Enhances Beta-secretase Activity

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2007 Jun 8

PMID 17553422

Citations 202

Authors

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

Affiliations

Soon will be listed here.

Abstract

Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Abeta 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 beta-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 Abeta. 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 beta-secretase activity. This mechanism may explain increased cerebral levels of BACE and Abeta following cerebral ischemia and existing in AD.

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