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Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice

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Abstract

Alzheimer's disease (AD) is an insidious neurodegenerative disorder representing a serious continuously escalating medico-social problem. The AD-associated progressive dementia is followed by gradual formation of amyloid plaques and neurofibrillary tangles in the brain. Though, converging evidence indicates apparent metabolic dysfunctions as key AD characteristic. In particular, late-onset AD possesses a clear metabolic signature. Considerable brain insulin signaling impairment and a decline in glucose metabolism are common AD attributes. Thus, positron emission tomography (PET) with glucose tracers is a reliable non-invasive tool for early AD diagnosis and treatment efficacy monitoring. Various approaches and agents have been trialed to modulate insulin signaling. Accumulating data point to arginase inhibition as a promising direction to treat AD via diverse molecular mechanisms involving, inter alia, the insulin pathway. Here, we use a transgenic AD mouse model, demonstrating age-dependent brain insulin signaling abnormalities, reduced brain insulin receptor levels, and substantial energy metabolism alterations, to evaluate the effects of arginase inhibition with Norvaline on glucose metabolism. We utilize fluorodeoxyglucose whole-body micro-PET to reveal a significant treatment-associated increase in glucose uptake by the brain tissue in-vivo. Additionally, we apply advanced molecular biology and bioinformatics methods to explore the mechanisms underlying the effects of Norvaline on glucose metabolism. We demonstrate that treatment-associated improvement in glucose utilization is followed by significantly elevated levels of insulin receptor and glucose transporter-3 expression in the mice hippocampi. Additionally, Norvaline diminishes the rate of Tau protein phosphorylation. Our results suggest that Norvaline interferes with AD pathogenesis. These findings open new avenues for clinical evaluation and innovative drug development.

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Data Availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Abbreviations

AD:

Alzheimer’s disease

3 × Tg:

Triple-transgenic mouse model of Alzheimer’s disease

PET:

Positron emission tomography

CT:

Computed tomography

Aβ:

Amyloid-beta

NFT:

Neurofibrillary tangles

CNS:

Central nervous system

GLUT:

Glucose transporter

WT:

Wild-type

KEGG:

Kyoto Encyclopedia of Genes and Genomes

BCAA:

Branched chain amino acid

OD:

Optical density

ANOVA:

Analysis of variance

HDAC:

Histone deacetylase

mTOR:

Mechanistic Target of Rapamycin

S6K1:

Ribosomal S6 kinase 1

PDPK1:

3-Phosphoinositide-dependent protein kinase-1

AKT:

RAC-alpha serine/threonine-protein kinase

CA:

Cornus Ammonis

SEM:

Standard error of the mean

mRNA:

Messenger ribonucleic acid

References

  1. 2020 Alzheimer's disease facts and figures. Alzheimers Dement. 2020. https://doi.org/10.1002/alz.12068.

  2. Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314(5800):777–781. https://doi.org/10.1126/science.1132814

    Article  CAS  PubMed  Google Scholar 

  3. Polis B, Samson AO (2019) A new perspective on Alzheimer's disease as a brain expression of a complex metabolic disorder. In: Wisniewski T (ed) Alzheimer's disease. Brisbane(AU)

  4. Avitan I, Halperin Y, Saha T, Bloch N, Atrahimovich D, Polis B et al (2021) Towards a consensus on Alzheimer’s disease comorbidity? J Clin Med. 10(19):10. https://doi.org/10.3390/jcm10194360

    Article  CAS  Google Scholar 

  5. Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 1147:180–195. https://doi.org/10.1196/annals.1427.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE (1995) A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 36(7):1238–1248

    CAS  PubMed  Google Scholar 

  7. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42(1):85–94. https://doi.org/10.1002/ana.410420114

    Article  CAS  PubMed  Google Scholar 

  8. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A et al (2012) Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 122(4):1316–1338. https://doi.org/10.1172/JCI59903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. de la Monte SM, Wands JR (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2(6):1101–1113. https://doi.org/10.1177/193229680800200619

    Article  PubMed  PubMed Central  Google Scholar 

  10. Petersen MC, Shulman GI (2018) Mechanisms of insulin action and insulin resistance. Physiol Rev 98(4):2133–2223. https://doi.org/10.1152/physrev.00063.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gray SM, Barrett EJ (2018) Insulin transport into the brain. Am J Physiol Cell Physiol 315(2):C125–C136. https://doi.org/10.1152/ajpcell.00240.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kobayashi M, Nikami H, Morimatsu M, Saito M (1996) Expression and localization of insulin-regulatable glucose transporter (GLUT4) in rat brain. Neurosci Lett 213(2):103–106. https://doi.org/10.1016/0304-3940(96)12845-7

    Article  CAS  PubMed  Google Scholar 

  13. Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295(2):E242–E253. https://doi.org/10.1152/ajpendo.90388.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Maher F, Simpson IA (1994) The GLUT3 glucose transporter is the predominant isoform in primary cultured neurons: assessment by biosynthetic and photoaffinity labelling. Biochem J 301(Pt 2):379–384. https://doi.org/10.1042/bj3010379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maher F, Davies-Hill TM, Simpson IA (1996) Substrate specificity and kinetic parameters of GLUT3 in rat cerebellar granule neurons. Biochem J 315(Pt 3):827–831. https://doi.org/10.1042/bj3150827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kyrtata N, Emsley HCA, Sparasci O, Parkes LM, Dickie BR (2021) A systematic review of glucose transport alterations in Alzheimer’s disease. Front Neurosci 15:626636. https://doi.org/10.3389/fnins.2021.626636

    Article  PubMed  PubMed Central  Google Scholar 

  17. Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P (1994) Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol 35(5):546–551. https://doi.org/10.1002/ana.410350507

    Article  CAS  PubMed  Google Scholar 

  18. Vannucci SJ, Maher F, Simpson IA (1997) Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21(1):2–21. https://doi.org/10.1002/(sici)1098-1136(199709)21:1%3c2::aid-glia2%3e3.0.co;2-c

    Article  CAS  PubMed  Google Scholar 

  19. Lesort M, Jope RS, Johnson GV (1999) Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J Neurochem 72(2):576–584. https://doi.org/10.1046/j.1471-4159.1999.0720576.x

    Article  CAS  PubMed  Google Scholar 

  20. Lesort M, Johnson GV (2000) Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience 99(2):305–316. https://doi.org/10.1016/s0306-4522(00)00200-1

    Article  CAS  PubMed  Google Scholar 

  21. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D et al (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 101(9):3100–3105. https://doi.org/10.1073/pnas.0308724101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tanaka M, Sawada M, Yoshida S, Hanaoka F, Marunouchi T (1995) Insulin prevents apoptosis of external granular layer neurons in rat cerebellar slice cultures. Neurosci Lett 199(1):37–40. https://doi.org/10.1016/0304-3940(95)12009-s

    Article  CAS  PubMed  Google Scholar 

  23. Umeda M, Hiramoto M, Watanabe A, Tsunoda N, Imai T (2015) Arginine-induced insulin secretion in endoplasmic reticulum. Biochem Biophys Res Commun 466(4):717–722. https://doi.org/10.1016/j.bbrc.2015.09.006

    Article  CAS  PubMed  Google Scholar 

  24. Thams P, Capito K (1999) L-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide. Eur J Endocrinol 140(1):87–93. https://doi.org/10.1530/eje.0.1400087

    Article  CAS  PubMed  Google Scholar 

  25. Leiss V, Flockerzie K, Novakovic A, Rath M, Schonsiegel A, Birnbaumer L et al (2014) Insulin secretion stimulated by L-arginine and its metabolite L-ornithine depends on Galpha(i2). Am J Physiol Endocrinol Metab 307(9):E800–E812. https://doi.org/10.1152/ajpendo.00337.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hu S, Han M, Rezaei A, Li D, Wu G, Ma X (2017) L-Arginine modulates glucose and lipid metabolism in obesity and diabetes. Curr Protein Pept Sci 18(6):599–608. https://doi.org/10.2174/1389203717666160627074017

    Article  CAS  PubMed  Google Scholar 

  27. Peters D, Berger J, Langnaese K, Derst C, Madai VI, Krauss M et al (2013) Arginase and arginine decarboxylase—where do the putative gate keepers of polyamine synthesis reside in rat brain? PLoS ONE 8(6):e66735. https://doi.org/10.1371/journal.pone.0066735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fonar G, Polis B, Meirson T, Maltsev A, Elliott E, Samson AO (2018) Intracerebroventricular administration of L-arginine improves spatial memory acquisition in triple transgenic mice via reduction of oxidative stress and apoptosis. Transl Neurosci 9:43–53. https://doi.org/10.1515/tnsci-2018-0009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Polis B, Srikanth KD, Elliott E, Gil-Henn H, Samson AO (2018) L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s Disease. Neurotherapeutics 15(4):1036–1054. https://doi.org/10.1007/s13311-018-0669-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kan MJ, Lee JE, Wilson JG, Everhart AL, Brown CM, Hoofnagle AN et al (2015) Arginine deprivation and immune suppression in a mouse model of Alzheimer’s disease. J Neurosci 35(15):5969–5982. https://doi.org/10.1523/JNEUROSCI.4668-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Polis B, Srikanth KD, Gurevich V, Gil-Henn H, Samson AO (2019) L-Norvaline, a new therapeutic agent against Alzheimer’s disease. Neural Regen Res 14(9):1562–1572. https://doi.org/10.4103/1673-5374.255980

    Article  PubMed  PubMed Central  Google Scholar 

  32. Polis B, Srikanth KD, Gurevich V, Bloch N, Gil-Henn H, Samson AO (2020) Arginase inhibition supports survival and differentiation of neuronal precursors in adult Alzheimer’s disease mice. Int J Mol Sci. https://doi.org/10.3390/ijms21031133

    Article  PubMed  PubMed Central  Google Scholar 

  33. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421. https://doi.org/10.1016/s0896-6273(03)00434-3

    Article  CAS  PubMed  Google Scholar 

  34. Bouter C, Bouter Y (2019) (18)F-FDG-PET in mouse models of Alzheimer’s disease. Front Med (Lausanne) 6:71. https://doi.org/10.3389/fmed.2019.00071

    Article  Google Scholar 

  35. Sancheti H, Akopian G, Yin F, Brinton RD, Walsh JP, Cadenas E (2013) Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer’s disease. PLoS ONE 8(7):e69830. https://doi.org/10.1371/journal.pone.0069830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D et al (2006) Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 47(6):999–1006

    CAS  PubMed  Google Scholar 

  37. Bellaver B, Rocha AS, Souza DG, Leffa DT, De Bastiani MA, Schu G et al (2019) Activated peripheral blood mononuclear cell mediators trigger astrocyte reactivity. Brain Behav Immun 80:879–888. https://doi.org/10.1016/j.bbi.2019.05.041

    Article  CAS  PubMed  Google Scholar 

  38. Wang J, Vasaikar S, Shi Z, Greer M, Zhang B (2017) WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Res 45(W1):W130–W137. https://doi.org/10.1093/nar/gkx356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27–30. https://doi.org/10.1093/nar/28.1.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dixit H, Kumar CS, Chaudhary R, Thaker D, Gadewal N, Dasgupta D (2021) Role of phosphorylation and hyperphosphorylation of tau in its interaction with betaalpha dimeric tubulin studied from a bioinformatics perspective. Avicenna J Med Biotechnol 13(1):24–34. https://doi.org/10.18502/ajmb.v13i1.4579

    Article  PubMed  PubMed Central  Google Scholar 

  41. He HJ, Wang XS, Pan R, Wang DL, Liu MN, He RQ (2009) The proline-rich domain of tau plays a role in interactions with actin. BMC Cell Biol 10:81. https://doi.org/10.1186/1471-2121-10-81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Eidenmuller J, Fath T, Maas T, Pool M, Sontag E, Brandt R (2001) Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau protein. Biochem J 357(Pt 3):759–767. https://doi.org/10.1042/0264-6021:3570759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li H, Ye D, Xie W, Hua F, Yang Y, Wu J et al (2018) Defect of branched-chain amino acid metabolism promotes the development of Alzheimer’s disease by targeting the mTOR signaling. Biosci Rep. https://doi.org/10.1042/BSR20180127

    Article  PubMed  PubMed Central  Google Scholar 

  44. Mondragon-Rodriguez S, Perry G, Luna-Munoz J, Acevedo-Aquino MC, Williams S (2014) Phosphorylation of tau protein at sites Ser(396–404) is one of the earliest events in Alzheimer’s disease and Down syndrome. Neuropathol Appl Neurobiol 40(2):121–135. https://doi.org/10.1111/nan.12084

    Article  CAS  PubMed  Google Scholar 

  45. Yanagawa H, Chung SH, Ogawa Y, Sato K, Shibata-Seki T, Masai J et al (1998) Protein anatomy: C-tail region of human tau protein as a crucial structural element in Alzheimer’s paired helical filament formation in vitro. Biochemistry 37(7):1979–1988. https://doi.org/10.1021/bi9724265

    Article  CAS  PubMed  Google Scholar 

  46. Polis B, Samson AO (2020) Role of the metabolism of branched-chain amino acids in the development of Alzheimer’s disease and other metabolic disorders. Neural Regen Res 15(8):1460–1470. https://doi.org/10.4103/1673-5374.274328

    Article  PubMed  PubMed Central  Google Scholar 

  47. Davoodi J, Drown PM, Bledsoe RK, Wallin R, Reinhart GD, Hutson SM (1998) Overexpression and characterization of the human mitochondrial and cytosolic branched-chain aminotransferases. J Biol Chem 273(9):4982–4989. https://doi.org/10.1074/jbc.273.9.4982

    Article  CAS  PubMed  Google Scholar 

  48. Serrano-Pozo A, Qian J, Muzikansky A, Monsell SE, Montine TJ, Frosch MP et al (2016) Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum. J Neuropathol Exp Neurol 75(6):516–526. https://doi.org/10.1093/jnen/nlw026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Khosravi M, Peter J, Wintering NA, Serruya M, Shamchi SP, Werner TJ et al (2019) 18F-FDG is a superior indicator of cognitive performance compared to 18F-Florbetapir in Alzheimer’s disease and mild cognitive impairment evaluation: a global quantitative analysis. J Alzheimers Dis 70(4):1197–1207. https://doi.org/10.3233/JAD-190220

    Article  CAS  PubMed  Google Scholar 

  50. Lee HG, Castellani RJ, Zhu X, Perry G, Smith MA (2005) Amyloid-beta in Alzheimer’s disease: the horse or the cart? Pathogenic or protective? Int J Exp Pathol 86(3):133–138. https://doi.org/10.1111/j.0959-9673.2005.00429.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Polis B, Karasik D, Samson AO (2021) Alzheimer’s disease as a chronic maladaptive polyamine stress response. Aging (Albany NY) 13(7):10770–10795. https://doi.org/10.18632/aging.202928

    Article  CAS  Google Scholar 

  52. Macdonald IR, DeBay DR, Reid GA, O’Leary TP, Jollymore CT, Mawko G et al (2014) Early detection of cerebral glucose uptake changes in the 5XFAD mouse. Curr Alzheimer Res 11(5):450–460. https://doi.org/10.2174/1567205011666140505111354

    Article  CAS  PubMed  Google Scholar 

  53. Bouter C, Henniges P, Franke TN, Irwin C, Sahlmann CO, Sichler ME et al (2018) (18)F-FDG-PET detects drastic changes in brain metabolism in the Tg4-42 model of Alzheimer’s disease. Front Aging Neurosci 10:425. https://doi.org/10.3389/fnagi.2018.00425

    Article  CAS  PubMed  Google Scholar 

  54. Wang Q, Lv C, Sun Y, Han X, Wang S, Mao Z et al (2018) The role of alpha-lipoic acid in the pathomechanism of acute ischemic stroke. Cell Physiol Biochem 48(1):42–53. https://doi.org/10.1159/000491661

    Article  CAS  PubMed  Google Scholar 

  55. Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A (2000) Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia 43(3):294–303. https://doi.org/10.1007/s001250050047

    Article  CAS  PubMed  Google Scholar 

  56. Dakhale GN, Chaudhari HV, Shrivastava M (2011) Supplementation of vitamin C reduces blood glucose and improves glycosylated hemoglobin in type 2 diabetes mellitus: a randomized, double-blind study. Adv Pharmacol Sci 2011:195271. https://doi.org/10.1155/2011/195271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Atrahimovich D, Samson AO, Khattib A, Vaya J, Khatib S (2018) Punicalagin decreases serum glucose levels and increases PON1 activity and HDL anti-inflammatory values in Balb/c mice fed a high-fat diet. Oxid Med Cell Longev 2018:2673076. https://doi.org/10.1155/2018/2673076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Malpica-Nieves CJ, Rivera-Aponte DE, Tejeda-Bayron FA, Mayor AM, Phanstiel O, Veh RW et al (2020) The involvement of polyamine uptake and synthesis pathways in the proliferation of neonatal astrocytes. Amino Acids 52(8):1169–1180. https://doi.org/10.1007/s00726-020-02881-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nicholson RM, Kusne Y, Nowak LA, LaFerla FM, Reiman EM, Valla J (2010) Regional cerebral glucose uptake in the 3xTG model of Alzheimer’s disease highlights common regional vulnerability across AD mouse models. Brain Res 1347:179–185. https://doi.org/10.1016/j.brainres.2010.05.084

    Article  CAS  PubMed  Google Scholar 

  60. Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ et al (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12(3):370–380. https://doi.org/10.1111/acel.12057

    Article  CAS  PubMed  Google Scholar 

  61. Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K et al (2013) Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS ONE 8(5):e62459. https://doi.org/10.1371/journal.pone.0062459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pei JJ, An WL, Zhou XW, Nishimura T, Norberg J, Benedikz E et al (2006) P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett 580(1):107–114. https://doi.org/10.1016/j.febslet.2005.11.059

    Article  CAS  PubMed  Google Scholar 

  63. Caccamo A, Branca C, Talboom JS, Shaw DM, Turner D, Ma L et al (2015) Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer’s Disease. J Neurosci 35(41):14042–14056. https://doi.org/10.1523/JNEUROSCI.2781-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ming XF, Rajapakse AG, Carvas JM, Ruffieux J, Yang Z (2009) Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline. BMC Cardiovasc Disord 9:12. https://doi.org/10.1186/1471-2261-9-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dalby KN, Morrice N, Caudwell FB, Avruch J, Cohen P (1998) Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK. J Biol Chem 273(3):1496–1505. https://doi.org/10.1074/jbc.273.3.1496

    Article  CAS  PubMed  Google Scholar 

  66. Simpson L, Li J, Liaw D, Hennessy I, Oliner J, Christians F et al (2001) PTEN expression causes feedback upregulation of insulin receptor substrate 2. Mol Cell Biol 21(12):3947–3958. https://doi.org/10.1128/MCB.21.12.3947-3958.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Moberg M, Apro W, Ekblom B, van Hall G, Holmberg HC, Blomstrand E (2016) Activation of mTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exercise. Am J Physiol Cell Physiol 310(11):C874–C884. https://doi.org/10.1152/ajpcell.00374.2015

    Article  PubMed  Google Scholar 

  68. McGee SL, van Denderen BJ, Howlett KF, Mollica J, Schertzer JD, Kemp BE et al (2008) AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57(4):860–867. https://doi.org/10.2337/db07-0843

    Article  CAS  PubMed  Google Scholar 

  69. Raichur S, Teh SH, Ohwaki K, Gaur V, Long YC, Hargreaves M et al (2012) Histone deacetylase 5 regulates glucose uptake and insulin action in muscle cells. J Mol Endocrinol 49(3):203–211. https://doi.org/10.1530/JME-12-0095

    Article  CAS  PubMed  Google Scholar 

  70. Xu K, Dai XL, Huang HC, Jiang ZF (2011) Targeting HDACs: a promising therapy for Alzheimer’s disease. Oxid Med Cell Longev 2011:143269. https://doi.org/10.1155/2011/143269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yang SS, Zhang R, Wang G, Zhang YF (2017) The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease. Transl Neurodegener 6:19. https://doi.org/10.1186/s40035-017-0089-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shah K, Lahiri DK (2014) Cdk5 activity in the brain - multiple paths of regulation. J Cell Sci 127(Pt 11):2391–2400. https://doi.org/10.1242/jcs.147553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kanungo J, Zheng YL, Amin ND, Pant HC (2009) Targeting Cdk5 activity in neuronal degeneration and regeneration. Cell Mol Neurobiol 29(8):1073–1080. https://doi.org/10.1007/s10571-009-9410-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J et al (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38(4):555–565. https://doi.org/10.1016/s0896-6273(03)00259-9

    Article  CAS  PubMed  Google Scholar 

  75. Saito T, Oba T, Shimizu S, Asada A, Iijima KM, Ando K (2019) Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262. Hum Mol Genet 28(18):3062–3071. https://doi.org/10.1093/hmg/ddz120

    Article  CAS  PubMed  Google Scholar 

  76. Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M et al (2005) Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med 11(10):1104–1108. https://doi.org/10.1038/nm1299

    Article  CAS  PubMed  Google Scholar 

  77. Wu H, Wu ZG, Shi WJ, Gao H, Wu HH, Bian F et al (2019) Effects of progesterone on glucose uptake in neurons of Alzheimer’s disease animals and cell models. Life Sci 238:116979. https://doi.org/10.1016/j.lfs.2019.116979

    Article  CAS  PubMed  Google Scholar 

  78. Li X, Han H, Hou R, Wei L, Wang G, Li C et al (2013) Progesterone treatment before experimental hypoxia-ischemia enhances the expression of glucose transporter proteins GLUT1 and GLUT3 in neonatal rats. Neurosci Bull 29(3):287–294. https://doi.org/10.1007/s12264-013-1298-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Guiochon-Mantel A, Lescop P, Christin-Maitre S, Loosfelt H, Perrot-Applanat M, Milgrom E (1991) Nucleocytoplasmic shuttling of the progesterone receptor. EMBO J 10(12):3851–3859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hagan CR, Daniel AR, Dressing GE, Lange CA (2012) Role of phosphorylation in progesterone receptor signaling and specificity. Mol Cell Endocrinol 357(1–2):43–49. https://doi.org/10.1016/j.mce.2011.09.017

    Article  CAS  PubMed  Google Scholar 

  81. Boucher J, Kleinridders A, Kahn CR (2014) Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a009191

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We gratefully acknowledge Dr. Zohar Gavish for his help with immunohistochemistry.

Funding

This research was supported by Marie Curie CIG Grant 322113, Leir Foundation Grant, Ginzburg Family Foundation Grant, and Katz Foundation Grant (all to AOS).

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Authors and Affiliations

  1. Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, 1311502, Safed, Israel

    Baruh Polis, Vyacheslav Gurevich, Kolluru D. Srikanth, Michael Assa & Abraham O. Samson

  2. Department of Computer Science, Bioengineering, Robotics and System Engineering (DIBRIS), University of Genoa, Genoa, Italy

    Margherita Squillario

  3. Laboratory of Molecular and Behavioral Neuroscience, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

    Kolluru D. Srikanth

  4. The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

    Vyacheslav Gurevich & Michael Assa

Authors
  1. Baruh Polis
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  2. Margherita Squillario
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  3. Vyacheslav Gurevich
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  4. Kolluru D. Srikanth
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  5. Michael Assa
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  6. Abraham O. Samson
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Contributions

BP and AS designed the experiments. BP was involved in all the aspects of the work and wrote the manuscript. KDS assisted in tissue sampling, western blot, immunohistochemistry, and initial data analysis. MS assisted in conducting the in-silico part. VG assisted in PET-CT experiments and statistical analysis. MA assisted in data analysis. AOS conceived, designed, supervised the experiments, and edited the manuscript.

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Correspondence to Baruh Polis.

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Conflict of interest

The authors declare no conflicts of interest.

Ethical Approval

The study was approved by the Bar-Ilan University Animal Care and Use Committee (approval No. 82–10-2017) on October 1, 2017.

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Not applicable.

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Supplementary Information

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Body weight evolution curves of the control and treated mice. Data are shown as mean values ± SEM. (TIF 409 KB)

11064_2021_3519_MOESM2_ESM.docx

Table S1. Selected results of the antibody array. Only proteins with a significant (p < 0.05) fold change from the control (CFC) are displayed. The cut-off was set at ±45% change (DOCX 28 KB)

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Polis, B., Squillario, M., Gurevich, V. et al. Effects of Chronic Arginase Inhibition with Norvaline on Tau Pathology and Brain Glucose Metabolism in Alzheimer's Disease Mice. Neurochem Res 47, 1255–1268 (2022). https://doi.org/10.1007/s11064-021-03519-3

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  • DOI: https://doi.org/10.1007/s11064-021-03519-3

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