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TAG-1 is an inhibitor of TGFbeta2-induced neuronal death via amyloid beta precursor protein
Nobuyuki Tachi1, Yuichi Hashimoto, Mikiro Nawa
1Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Tokyo 160-8402, Japan.
Abstract:
Our earlier studies indicated that TGFbeta2-induced neuronal cell death by binding to the extracellular domain of amyloid beta precursor protein (APP) on the cell surface and by triggering an intracellular death signal pathway, mediated by a heterotrimeric G protein Go, Rac1/cdc42, ASK1, JNK, NADPH oxidase, and caspases in this order. Recently, transient axonal glycoprotein-1 (TAG-1), a glycophosphatidylinositol-linked protein, was identified as another natural ligand of APP. TAG-1 increases APP intracellular domain release and triggers FE65-dependent transcriptional activity in a gamma-secretase-dependent manner by binding to APP. In this study, we show that TAG-1 inhibits TGFbeta2-mediated neuronal cell death via APP by attenuating the binding of TGFbeta2 to APP in a gamma-secretase-independent manner. TAG-1 is expressed in murine hippocampal neurons at 8 weeks of age, but its expression is reduced at 8 and 20 months. These findings suggest that an age-related reduction of TAG-1 expression may predispose neurons to cell death, induced by the binding of TGFbeta2 to APP. This mechanism may contribute to the onset and the progression of Alzheimer's disease-relevant neuronal cell death.
Insights
Transient axonal glycoprotein-1 (TAG-1) protects neurons from TGFbeta2-induced cell death by preventing TGFbeta2 binding to amyloid precursor protein (APP). Age-related decreases in TAG-1 may increase Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor beta 2 (TGFbeta2) induces neuronal cell death by binding to amyloid precursor protein (APP) and activating an intracellular signaling cascade.
- Transient axonal glycoprotein-1 (TAG-1), a novel APP ligand, influences APP intracellular domain release and transcriptional activity.
Purpose of the Study:
- To investigate the role of TAG-1 in modulating TGFbeta2-mediated neuronal cell death via APP.
- To explore the potential link between age-related changes in TAG-1 expression and neuronal vulnerability in Alzheimer's disease.
Main Methods:
- Investigated the interaction between TAG-1, TGFbeta2, and APP in neuronal cells.
- Assessed the effect of TAG-1 on TGFbeta2 binding to APP using biochemical assays.
- Examined TAG-1 expression levels in murine hippocampal neurons at different ages.
Main Results:
- TAG-1 inhibits TGFbeta2-induced neuronal cell death by attenuating TGFbeta2 binding to APP in a gamma-secretase-independent manner.
- TAG-1 expression is present in young adult murine hippocampal neurons but decreases with age.
Conclusions:
- Age-related reduction in TAG-1 expression may render neurons more susceptible to TGFbeta2-induced cell death.
- This mechanism involving TAG-1, APP, and TGFbeta2 may contribute to Alzheimer's disease pathogenesis.
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