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High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease Via a Specific Tau Phosphorylation Pattern

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Abstract

Background

Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer’s disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown.

Objective

In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain.

Design

Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates.

Results

Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD.

Conclusion

These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.

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References

  1. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017;390:2673–2734. https://doi.org/10.1016/S0140-6736(17)31363-6

    Article  PubMed  Google Scholar 

  2. Takeda S, Sato N, Rakugi H, Morishita R. Molecular mechanisms linking diabetes mellitus and Alzheimer disease: beta-amyloid peptide, insulin signaling, and neuronal function. Mol Biosyst 2011;7:1822–1827. https://doi.org/10.1039/c0mb00302f

    Article  CAS  PubMed  Google Scholar 

  3. Takeda S, Sato N, Uchio-Yamada K, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A 2010;107:7036–7041. https://doi.org/10.1073/pnas.1000645107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Takeda S, Rakugi H, Morishita R. Roles of vascular risk factors in the pathogenesis of dementia. Hypertens Res 2020;43:162–167. https://doi.org/10.1038/s41440-019-0357-9

    Article  PubMed  Google Scholar 

  5. Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology 2011;77:1126–1134. https://doi.org/10.1212/WNL.0b013e31822f0435

    Article  CAS  PubMed  Google Scholar 

  6. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 1999;53:1937–1942. https://doi.org/10.1212/wnl.53.9.1937

    Article  CAS  PubMed  Google Scholar 

  7. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet 2011;377:1019–1031. https://doi.org/10.1016/S0140-6736(10)61349-9

    Article  PubMed  Google Scholar 

  8. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986;261:6084–6089.

    Article  CAS  PubMed  Google Scholar 

  9. Gómez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 1997;41:17–24. https://doi.org/10.1002/ana.410410106

    Article  PubMed  Google Scholar 

  10. Martin L, Latypova X, Wilson CM, et al. Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 2013;12:289–309. https://doi.org/10.1016/j.arr.2012.06.003

    Article  CAS  PubMed  Google Scholar 

  11. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 2001;98:6923–6928. https://doi.org/10.1073/pnas.121119298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Trojanowski JQ, Lee VM. Paired helical filament tau in Alzheimer’s disease. The kinase connection. Am J Pathol 1994;144:449–453.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Clodfelder-Miller BJ, Zmijewska AA, Johnson GV, Jope RS. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes 2006;55:3320–3325. https://doi.org/10.2337/db06-0485

    Article  CAS  PubMed  Google Scholar 

  14. Leboucher A, Laurent C, Fernandez-Gomez FJ, et al. Detrimental effects of diet-induced obesity on τ pathology are independent of insulin resistance in τ transgenic mice. Diabetes 2013;62:1681–1688. https://doi.org/10.2337/db12-0866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nobuhara CK, DeVos SL, Commins C, et al. Tau antibody targeting pathological species blocks neuronal uptake and interneuron propagation of tau in vitro. Am J Pathol 2017;187:1399–1412. https://doi.org/10.1016/j.ajpath.2017.01.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wesseling H, Mair W, Kumar M, et al. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease. Cell 2020;183:1699–1713.e13. https://doi.org/10.1016/j.cell.2020.10.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yoshiyama Y, Higuchi M, Zhang B, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007;53:337–351. https://doi.org/10.1016/j.neuron.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  18. Ayala JE, Samuel VT, Morton GJ, et al. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 2010;3:525–534. https://doi.org/10.1242/dmm.006239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guyenet SJ, Furrer SA, Damian VM, Baughan TD, La Spada AR, Garden GA. A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J Vis Exp 2010;39:1787. https://doi.org/10.3791/1787

    Google Scholar 

  20. Lei P, Ayton S, Moon S, et al. Motor and cognitive deficits in aged tau knockout mice in two background strains. Mol Neurodegener 2014;9:29. https://doi.org/10.1186/1750-1326-9-29

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kawashima Y, Watanabe E, Umeyama T, et al. Optimization of data-independent acquisition mass spectrometry for deep and highly sensitive proteomic analysis. Int J Mol Sci 2019;20:5932. https://doi.org/10.3390/ijms20235932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Searle BC, Pino LK, Egertson JD, et al. Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry. Nat Commun 2018;9:5128. https://doi.org/10.1038/s41467-018-07454-w

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sato H, Ishida S, Toda K, et al. New approaches to mechanism analysis for drug discovery using DNA microarray data combined with KeyMolnet. Curr Drug Discov Technol 2005;2:89–98. https://doi.org/10.2174/1570163054064701

    Article  CAS  PubMed  Google Scholar 

  24. Satoh J, Tabunoki H, Arima K. Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus. Dis Markers 2009;27:239–252. https://doi.org/10.3233/DMA-2009-0670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Takeda S. Tau propagation as a diagnostic and therapeutic target for dementia: potentials and unanswered questions. Front Neurosci 2019;13:1274. https://doi.org/10.3389/fnins.2019.01274

    Article  PubMed  PubMed Central  Google Scholar 

  26. Takeda S, Wegmann S, Cho H, et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat Commun 2015;6:8490. https://doi.org/10.1038/ncomms9490

    Article  CAS  PubMed  Google Scholar 

  27. Götz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001;293:1491–1495. https://doi.org/10.1126/science.1062097

    Article  PubMed  Google Scholar 

  28. Barthélemy NR, Li Y, Joseph-Mathurin N, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med 2020;26:398–407. https://doi.org/10.1038/s41591-020-0781-z

    Article  PubMed  PubMed Central  Google Scholar 

  29. Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol 1995;131:1327–1340. https://doi.org/10.1083/jcb.131.5.1327

    Article  CAS  PubMed  Google Scholar 

  30. Brandt R, Trushina NI, Bakota L. Much more than a cytoskeletal protein: physiological and pathological functions of the non-microtubule binding region of tau. Front Neurol 2020;11:590059. https://doi.org/10.3389/fneur.2020.590059

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li T, Paudel HK. Glycogen synthase kinase 3beta phosphorylates Alzheimer’s disease-specific Ser396 of microtubule-associated protein tau by a sequential mechanism. Biochemistry 2006;45:3125–3133. https://doi.org/10.1021/bi051634r

    Article  CAS  PubMed  Google Scholar 

  32. Zhou XW, Winblad B, Guan Z, Pei JJ. Interactions between glycogen synthase kinase 3beta, protein kinase B, and protein phosphatase 2A in tau phosphorylation in mouse N2a neuroblastoma cells. J Alzheimers Dis 2009;17:929–937. https://doi.org/10.3233/JAD-2009-1113

    Article  CAS  PubMed  Google Scholar 

  33. Zheng-Fischhöfer Q, Biernat J, Mandelkow EM, Illenberger S, Godemann R, Mandelkow E. Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur J Biochem 1998;252:542–552. https://doi.org/10.1046/j.1432-1327.1998.2520542.x

    Article  PubMed  Google Scholar 

  34. Yoshimura Y, Ichinose T, Yamauchi T. Phosphorylation of Tau protein to sites found in Alzheimer’s disease brain is catalyzed by Ca2+/calmodulin-dependent protein kinase II as demonstrated tandem mass spectrometry. Neurosci Lett 2003;353:185–188. https://doi.org/10.1016/j.neulet.2003.09.037

    Article  CAS  PubMed  Google Scholar 

  35. Xu J, Sato S, Okuyama S, et al. Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice. FASEB J 2010;24:2904–2915. https://doi.org/10.1096/fj.09-150144

    Article  CAS  PubMed  Google Scholar 

  36. Taniguchi T, Kawamata T, Mukai H, et al. Phosphorylation of tau is regulated by PKN. J Biol Chem 2001;276:10025–10031. https://doi.org/10.1074/jbc.M007427200

    Article  CAS  PubMed  Google Scholar 

  37. Tavares IA, Touma D, Lynham S, et al. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate Tau protein and are activated in tangle-bearing neurons in Alzheimer disease. J Biol Chem 2013;288:15418–15429. https://doi.org/10.1074/jbc.M112.448183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Propson NE, Roy ER, Litvinchuk A, Köhl J, Zheng H. Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. J Clin Invest 2021;131:e140966. https://doi.org/10.1172/JCI140966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by Center for Medical Research and Education, Graduate School of Medicine, Osaka University. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants, including a Grant-in-Aid for Young Scientists (A) (17H05080) and a Grant-in-Aid for Scientific Research (B) (21H02828) awarded to S.T., and a research grant from the Cell Science Research Foundation awarded to S.T.

Funding

The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or in the review or approval of the manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Y. Ito, Shuko Takeda, K. Miki & Ryuichi Morishita

  2. Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, 3-16-21 Miyanosaka, Hirakata, Osaka, Japan

    Y. Ito, Shuko Takeda & A. Oyama

  3. Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, Japan

    T. Nakajima, A. Oyama, H. Takeshita, Y. Takami, Y. Takeya & H. Rakugi

  4. Department of Clinical Nursing, Division of Health Sciences, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, Japan

    Y. Takeya

  5. Department of Neurology, Department of Health Development and Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, Japan

    M. Shimamura

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  1. Y. Ito
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Corresponding authors

Correspondence to Shuko Takeda or Ryuichi Morishita.

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Conflict of Interest Statement: The authors declare no conflicts of interest.

Ethical standards: All animal procedures were performed in Osaka University School of Medicine after the approval of the study protocol by the Animal Experiments Committee of Osaka University, Osaka, Japan (decision reference number 29-046-015). This study protocol was reviewed and approved by the Osaka University Living Modified Organisms (LMO) Research Safety Committee (approval number 04232). All animal experiments comply with the ARRIVE guidelines and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Supplemental Information: High-fat diet-induced diabetic conditions exacerbate cognitive impairment in a mouse model of Alzheimer’s disease via a specific tau phosphorylation pattern

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Ito, Y., Takeda, S., Nakajima, T. et al. High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease Via a Specific Tau Phosphorylation Pattern. J Prev Alzheimers Dis 11, 138–148 (2024). https://doi.org/10.14283/jpad.2023.85

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  • DOI: https://doi.org/10.14283/jpad.2023.85

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