Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.
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.
Tesco
Giuseppina
G
Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA. tescog@helix.mgh.harvard.edu
Koh
Young Ho
YH
Kang
Eugene L
EL
Cameron
Andrew N
AN
Das
Shinjita
S
Sena-Esteves
Miguel
M
Hiltunen
Mikko
M
Yang
Shao-Hua
SH
Zhong
Zhenyu
Z
Shen
Yong
Y
Simpkins
James W
JW
Tanzi
Rudolph E
RE
D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000201:enzymology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000201:enzymology / Q000503:physiopathology; D002417:Cattle; D002478:Cells, Cultured; D004285:Dogs; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C407306:GGA adaptor proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D020727:ADP-Ribosylation Factors