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Increased Phosphorylation of Tau and Synaptic Protein Loss in the Aged Transgenic Mice Expressing Familiar Alzheimer’s Disease-Linked Presenilin 1 Mutation

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Abstract

Mutations in presenilin 1 (PS-1) are associated with most early-onset familiar Alzheimer’s disease (AD). Previous studies have demonstrated that PS-1 mutations enhance the production of beta-amyloid (Aβ). In this study, we further examined the in vivo effects of PS-1 mutation on tau and synapse protein markers. The data showed that the phosphorylation of tau at Ser396, Ser404, Thr231 and Tau-1 (Ser198/199/202) epitopes was significantly increased in hippocampus of the aged (twenty-one and a half-month-old) transgenic mice expressing PS-1 (L235P) compared to that of the age-matched wild-type littermates (WTs). Concurrently, a significant decrease in the phosphorylation of glycogen synthase kinase (GSK)-3β at Ser9 was observed. The above changes were not observed in the young transgenic mice (6–8 months old). No significant changes in the levels of cyclin-dependent kinase (CDK)-5, its co-activator p35, and phosphorylation of protein phosphatase (PP)-2A catalytic subunit at Tyrosine 307 (Y307), a crucial site regulating the activity of PP-2A, were observed both in the young and aged transgenic mice compared to that of WTs. Furthermore, we also observed that the levels of presynaptic synaptophysin were significantly decreased but postsynaptic density protein (PSD)-95 were not significantly altered in hippocampus of the aged transgenic mice. No significant changes of synaptophysin or PSD-95 were observed in the brains of the young transgenic mice. Our data indicate that the L235P PS-1 mutation can induce Alzheimer-like tau hyperphosphorylation and synaptic protein loss, as well as increased production of Aβ.

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Abbreviations

AD:

Alzheimer’s disease

PS-1:

Presenilin 1

(GSK)-3β:

Glycogen synthase kinase-3β

CDK-5:

Cyclin-dependent kinase-5

PP-2A:

Protein phosphatase-2A

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Acknowledgments

This study was supported by the grant from National Natural Science Foundation of China (NSFC, 30700277).

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Authors and Affiliations

  1. Toxicology Laboratory, Shenzhen Centre for Disease Control and Prevention, 8 Longyuan Road, Nanshan District, 518055, Shenzhen, China

    Xifei Yang & Jianjun Liu

  2. Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Ying Yang

  3. Time Medical Systems, No. 2, Science Park West Avenue, Hong Kong, China

    Geng Li & Edward Yang

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  1. Xifei Yang
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Corresponding author

Correspondence to Xifei Yang.

Additional information

Xifei Yang and Ying Yang equally contributed to the work.

Electronic supplementary material

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11064_2011_575_MOESM1_ESM.pdf

Supplementary Fig. 1. Phosphorylation of tau was not significantly altered in hippocampus of the young transgenic mice. The phosphorylation level of tau was normalized against total tau probed by Tau-5. Phosphorylation of tau at Ser396, Ser404, Thr231 and Tau-1 (Ser198/199/202) Ser 262 epitopes in hippocampus of the young transgenic mice was not significantly altered. Quantitative analysis showed the relative intensities of tau at above sites. (n=4). (PDF 60 kb)

11064_2011_575_MOESM2_ESM.pdf

Supplementary Fig. 2. The levels of p-GSK-3β in hippocampus of the young transgenic mice were not altered. The levels of p-GSK-3β/GSK-3β in hippocampus of the young transgenic mice were determined by Western blot analysis. Quantitative analysis showed the relative intensity of p-GSK-3β/total GSK-3β. (n=4). (PDF 39 kb)

11064_2011_575_MOESM3_ESM.pdf

Supplementary Fig. 3. The levels of synaptophysin and PSD-95 in hippocampus of the young transgenic mice were not altered. The levels of synaptophysin and PSD-95 in hippocampus of the young transgenic mice were determined by Western blot analysis. The levels of synaptophysin and PSD-95 were normalized against β-actin. Quantitative analysis showed the relative intensities of synaptophysin and PSD-95. (n=4). (PDF 47 kb)

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Yang, X., Yang, Y., Liu, J. et al. Increased Phosphorylation of Tau and Synaptic Protein Loss in the Aged Transgenic Mice Expressing Familiar Alzheimer’s Disease-Linked Presenilin 1 Mutation. Neurochem Res 37, 15–22 (2012). https://doi.org/10.1007/s11064-011-0575-2

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  • DOI: https://doi.org/10.1007/s11064-011-0575-2

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