Decreased expression of GGA3 Protein in Alzheimer's disease frontal cortex and increased co-distribution of BACE with the amyloid precursor protein

作者：Santosa Claudia; Rasche Stefanie; Barakat Adel; Bellingham Shayne A; Ho Michael; Tan Jiangli; Hill Andrew F; Masters Colin L; McLean Catriona; Evin Genevieve^*

来源：Neurobiology of Disease, 2011, 43(1): 176-183.

DOI：10.1016/j.nbd.2011.03.009

• BACE1
• Secretase
• Amyloid precursor protein
• Alzheimer's disease

BACE initiates the amyloidogenic processing of the amyloid precursor protein (APP) that results in the production of A beta peptides associated with Alzheimer's disease (AD). Previous studies have indicated that BACE is elevated in the frontal cortex of AD patients. Golgi-localized gamma-ear containing ADP ribosylation factor-binding proteins (GGA) control the cellular trafficking of BACE and may alter its levels. To investigate a link between BACE and GGA expression in AD, frontal cortex samples from AD (N = 20) and healthy, age-matched controls (HC. N = 17) were analyzed by immunoblotting. After normalization to the neuronal marker beta-tubulin III, the data indicate an average two-fold increase of BACE protein (p = 0.01) and a 64% decrease of GGA3 in the AD group compared to the HC (p = 0.006). GGA1 levels were also decreased in AD, but a statistical significance was not achieved. qRT-PCR analysis of GGA3 mRNA showed no difference between AD and HC. There was a strong correlation between GGA1 and GGA3 in both AD and HC, but no correlation between BACE and GGA levels. Subcellular fractionation of AD cortex with low levels of GGA proteins showed an alteration of BACE distribution and extensive co-localization with APP. These data suggest that altered compartmentalization of BACE in AD promotes the amyloidogenic processing of APP.

• 出版日期2011-7