Article

Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.

Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Neuron (impact factor: 14.74). 07/2007; 54(5):721-37. DOI:10.1016/j.neuron.2007.05.012 pp.721-37
Source: PubMed

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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  • Article: Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease.
    A LeBlanc, H Liu, C Goodyer, C Bergeron, J Hammond
    [show abstract] [hide abstract]
    ABSTRACT: Neuronal cell death, neurofibrillary tangles, and amyloid beta peptide (Abeta) deposition depict Alzheimer's disease (AD) pathology, but neuronal loss correlates best with dementia. We have shown that increased production of Abeta is a consequence of neuronal apoptosis, suggesting that apoptosis activates proteases involved in amyloid precursor protein (APP) processing. Here, we investigate key effectors of cell death, caspases, in human neuronal apoptosis and APP processing. We find that caspase-6 is activated and responsible for neuronal apoptosis by serum deprivation. Caspase-6 activity precedes the time of commitment to neuronal apoptosis by 10 h, indicating possible activity without subsequent apoptosis. Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Abeta. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Abeta-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons. A pulse-chase experiment reveals a precursor-product relationship between Capp6.5, intracellular Abeta, and secreted Abeta, indicating a potential alternate amyloidogenic pathway. Caspase-6 proenzyme is present in adult human brain tissue, and the p10 active caspase-6 fragment is detected in AD brain tissue. These results indicate a possible alternate pathway for APP amyloidogenic processing in human neurons and a potential implication for this pathway in the neuronal demise of AD.
    Journal of Biological Chemistry 09/1999; 274(33):23426-36. · 4.77 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

Abeta
 
AD brain
 
AD brain samples
 
AD)-associated Abeta protein
 
adaptor protein
 
Alzheimer's disease
 
BACE
 
BACE levels
 
BACE trafficking
 
beta-secretase activity
 
Beta-site APP-cleaving enzyme
 
caspase activation
 
cerebral ischemia
 
cerebral levels
 
GGA3-dependent mechanism regulating BACE levels
 
increases
 
inversely correlated
 
molecular mechanism responsible
 
stress-related protease
 
upregulated