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O1‐03–02: Analyzing the endogenous roles of GSK‐3 isoforms in APP processing in GSK‐3 deficient cells
Author(s) -
Popkie Anthony,
Buescher Jessica L.,
Miranda Carlos J.,
Kaspar Brian K.,
Phiel Christopher J.,
Doble Bradley W.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.230
Subject(s) - gsk 3 , gene isoform , gsk3b , gene knockdown , embryonic stem cell , phosphorylation , genetically modified mouse , biology , knockout mouse , transgene , microbiology and biotechnology , neural stem cell , kinase , chemistry , stem cell , biochemistry , cell culture , genetics , gene
Alzheimer’s BACE1. Increased expression of RTN3 in culture reduces the production of -amyloid peptide (A ). However, RTN3 can also form high-molecular-weight RTN3 aggregates upon aberrant accumulation, and the increased RTN3 aggregation correlates with the formation of RTN3 immunoreactive dystrophic neurites (RIDNs) in brains of Alzheimer’s cases. Transgenic mice expressing RTN3 develop RIDNs in their hippocampal CA1 region but not in their cerebral cortex and the other hippocampal regions. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Methods: By taking advantage of this unique subregional phenotype, we bred RTN3 transgenic mice with transgenic mice expressing FAD mutant APP and PS1, and asked two questions: 1) whether increased expression of RTN3 could reduce A plaques in the cerebral cortex,; 2) whether the formation of hippocampal RIDNs would affect A deposition. Results: Our results demonstrated that the dystrophic -amyloid deposition in the cortical region, the hippocampal CA3 and dentate gyrus was significantly reduced in trigenic mice. However, in the hippocampal CA1 region of trigenic mice where RIDNs occurred prior to the amyloid deposition, the reduction of amyloid deposition was not evident. We also found that RTN3 altered BACE1 intracellular trafficking as a mechanism for inhibition of BACE1 activity. This study not only provides the first evidence that increased expression of RTN3 can inhibit the dystrophic -amyloid deposition in vivo but also suggests that preformed RIDNs contribute to -amyloid deposition. Conclusions: Together, our data suggests that RTN3 may have differential roles in AD pathogenesis: in negatively regulating A plaque formation and inducing neuritic dystrophy. Our results suggest that inhibition of RTN3 aggregation is likely more beneficial by reducing both amyloid deposition and RIDNs.