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. 2023 Sep 13:15:1241750.
doi: 10.3389/fnagi.2023.1241750. eCollection 2023.

The γ-Adducin 1-357 fragment promotes tau pathology

Honglu Yu  1 , Min Xiong  1 , Congcong Liu  1 , Danhao Xia  1 , Lanxia Meng  1 , Zhentao Zhang  1   2
Affiliations

The γ-Adducin 1-357 fragment promotes tau pathology

Honglu Yu et al. Front Aging Neurosci. .

Abstract

Background: Tau phosphorylation is a pathological hallmark of Alzheimer's disease (AD). Previously, we reported that the γ-adducin 1-357 fragment is present in the brains of AD patients. However, it remains unknown how γ-adducin regulates tau phosphorylation.

Objective: The aim of this project is to investigate the effects of the γ-adducin 1-357 fragment on tau phosphorylation and the kinases involved in this process.

Methods: Full-length γ-adducin or the γ-adducin 1-357 fragment was expressed in HEK293 cells, SH-SY5Y cells, and primary neurons. The phosphorylation of tau Ser396 was determined using Western blot and immunofluorescence. Tau P301S transgenic mice were injected with adeno-associated virus encoding full-length γ-adducin or γ-adducin 1-357 fragment to determine the phosphorylation of tau.

Results: The γ-adducin 1-357 fragment enhances tau phosphorylation at Ser396. Additionally, the expression of the γ-adducin 1-357 fragment leads to the activation of glycogen synthase kinase-3β (GSK-3β). This effect was mitigated by the GSK-3β inhibitor 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8).

Conclusion: The γ-adducin 1-357 fragment enhances tau phosphorylation by activating GSK3β. These results support that the fragmentation of γ-adducin may play a pivotal role in tau pathology.

Keywords: 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; Alzheimer’s disease; glycogen synthase kinase-3β; tau phosphorylation; γ-adducin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
γ-Adducin 1–357 enhances tau phosphorylation in vitro. (A,B) Western blot analysis of tau phosphorylation at Ser396 in HEK293 cells co-transfected with HA-tau and GST-vector, GST-γ-adducin, or GST-γ-adducin 1–357. (C,D) Western blot analysis of tau phosphorylation at Ser396 in SH-SY5Y cells. Data were presented as mean ± SD, n = 6 independent experiments. n.s. not significant, ***p < 0.001, ****p < 0.0001, by one-way ANOVA.
Figure 2
Figure 2
γ-Adducin 1–357 promotes tau phosphorylation in primary neurons. (A,B) Western blot analysis of tau phosphorylation at Ser396 in primary neurons infected with AAV-GFP, AAV-GFP-γ-adducin, and AAV-GFP-γ-adducin 1–357. Data were presented as mean ± SD, n = 6 independent experiments. n.s. not significant, ****p < 0.0001 by one-way ANOVA. (C) Immunofluorescence of phosphorylated tau (red) along with GFP-tag (green) in primary neurons. Scale bar, 20 μm. Data were presented as mean ± SD, n = 6 independent experiments. ****p < 0.0001. AU, arbitrary units.
Figure 3
Figure 3
GSK-3β mediates tau phosphorylation induced by γ-adducin 1–357. (A,B) Western blot of the levels of CDK5 (Cyclin-dependent kinase 5), Akt (Protein kinase B), and GSK-3β (Glycogen synthase kinase-3β) in primary neurons. (C,D) Western blot analysis of the levels of GSK3β, p-tau Ser396 (phosphorylated tau at Ser396), and total tau in primary neurons with or without TDZD-8 (specific kinase inhibitor TDZD-8). Data were presented as mean ± SD, n = 6 independent experiments. n.s. not significant, **p < 0.01, ***p < 0.001, ****p < 0.0001 by one-way ANOVA.
Figure 4
Figure 4
γ-Adducin 1–357 enhances tau phosphorylation in a mouse model of AD. (A,B) Western blot analysis of phosphorylated tau at Ser396 in 6 month-old tau P301S mice injected with AAV-EGFP, AAV-EGFP-γ-adducin, and AAV-EGFP-γ-adducin 1–357. Data were presented as mean ± SD, n = 6 mice per group. n.s. not significant, ****p < 0.0001 by one-way ANOVA. (C,D) Immunofluorescence of phosphorylated tau (red) with DAPI staining (blue) in various brain regions. Scale bar, 20 μm. Data were presented as mean ± SD, n = 4 mice per group. *p < 0.05, ***p < 0.001, ****p < 0.0001. AU, arbitrary units.
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