Alzheimer's disease genetic mutation evokes ultrastructural alterations: Correlation to an intracellular A beta deposition and the level of GSK-3 beta-P(Y216) phosphorylated form

作者：Pajak Beata^*; Songin Martyna; Strosznajder Joanna B; Gajkowska Barbara

来源：NeuroToxicology, 2009, 30(4): 581-588.

DOI：10.1016/j.neuro.2009.05.008

• Amyloid-beta
• Swedish double mutation
• Ultrastructure
• GSK-3 beta
• PC12 cells

Herein we demonstrate that PC12 cells, which overexpress human wild-type amyloid-beta precursor protein (A beta PPwt) or A beta PP bearing double Swedish mutation (A beta PPsw), reveal phenotype characteristic for Alzheimer's disease (AD). The examination of cell ultrastructure showed the presence of peptide aggregates within the cells, activation of endosomal-lysosomal system and extensive exocytosis. Furthermore, the autophagy induction was also characteristic hallmark of amyloid-beta-induced cytotoxicity. Morphological changes were positively correlated with the extent of phosphorylated glycogen synthase kinase-3 beta (phospho-Tyr(216)-GSK-3 beta, GSK-3 beta-P(Y216)). The activity of GSK-3 beta is believed to cause tau protein hyper-phosphorylation, increased amyloid-beta production and local plaque-associated microglial-mediated inflammatory responses. All of them are symptomatic for AD. In our studies, the highly significant Y216 phosphorylation and over-expression of total GSK-3 beta were observed in A beta PPsw-transfected PC12 cells. In addition, the immuocytochemical analysis showed co-localization of GSK-3 beta-P(Y216) and amyloid-beta deposits. Thus, our data support a functional role of GSK-3 beta in A beta PP processing, further implicating this kinase in the amyloid-beta-dependent pathogenesis.

• 出版日期2009-7