Skip to main content

Advertisement

SpringerLink
Log in

Ang(1–7) exerts Nrf2-mediated neuroprotection against amyloid beta-induced cognitive deficits in rodents

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder with cognitive deficits in an individual. Ang(1–7) exhibits neuroprotection against amyloid beta (Aβ)-induced mitochondrial dysfunction and neurotoxicity in experimental conditions. Further, Ang(1–7) also exhibits nrf2-mediated antioxidant activity in experimental conditions. However, its therapeutic role on nrf2-mediated mitochondrial function is yet to be established in the Aβ-induced neurotoxicity. The experimental dementia was induced in the male rats by intracerebroventricular administration of Aβ(1–42) on day-1 (D-1) of the experimental schedule of 14 days. Ang(1–7) was administered once daily from D-1 toD-14 to the Aβ-challenged rodents. Ang(1–7) attenuated Aβ-induced increase in escape latency and decrease in the time spent in the target quadrant during Morris water maze and percentage of spontaneous alteration behavior during Y-maze tests in the rats. Further, Ang(1–7) attenuated Aβ-induced cholinergic dysfunction in terms of decrease in the level of acetylcholine and activity of choline acetyltransferase, and increase in the activity of acetylcholinesterase, and increase in the level of Aβ in rat hippocampus, pre-frontal cortex and amygdala. Furthermore, Ang(1–7) reversed Aβ-induced decrease in the mitochondrial function, integrity and bioenergetics in all brain regions. Additionally, Ang(1–7) attenuated Aβ-induced increase in the extent of apoptosis and decrease in the level of heme oxygenase-1 in all selected brain regions. Trigonelline significantly abolished the therapeutic effectiveness of Ang(1–7) on Aβ-induced alterations in the behavioral, neurochemicals and molecular observations in the animals. Ang(1–7) may exhibit nrf2-mediated neuroprotection in these rodents. Hence, Ang(1–7) could be a potential therapeutic option in the pharmacotherapy of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Singh A, Kumar A (2016) Comparative analysis of intrahippocampal amyloid beta (1–42) and intracerbroventricular streptozotocin models of Alzheimer’s disease: possible behavioral, biochemical, mitochondrial, cellular and histopathological evidences. J Alzheimer’s Dis Park 06:1–7. https://doi.org/10.4172/2161-0460.1000208

    Article  Google Scholar 

  2. Rajmohan R, Reddy PH (2017) Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons. J Alzheimer’s Dis 57:975–999

    Article  CAS  Google Scholar 

  3. Grimaldi M, Di Marino S, Florenzano F et al (2016) β-Amyloid-acetylcholine molecular interaction: new role of cholinergic mediators in anti-Alzheimer therapy? Future Med Chem 8:1179–1189. https://doi.org/10.4155/fmc-2016-0006

    Article  CAS  PubMed  Google Scholar 

  4. Lambert MP, Barlow AK, Chromy BA et al (1998) Diffusible, non fibrillar ligands derived from A 1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci 95:6448–6453. https://doi.org/10.1073/pnas.95.11.6448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mangialasche F, Solomon A, Winblad B et al (2010) Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 9:702–716

    Article  CAS  Google Scholar 

  6. Benilova I, Karran E, De Strooper B (2012) The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15:349–357. https://doi.org/10.1038/nn.3028

    Article  CAS  PubMed  Google Scholar 

  7. Giacobini E, Gold G (2013) Alzheimer disease therapy—moving from amyloid-β to tau. Nat Rev Neurol 9:677–686. https://doi.org/10.1038/nrneurol.2013.223

    Article  CAS  Google Scholar 

  8. Goure WF, Krafft GA, Jerecic J, Hefti F (2014) Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimer’s Res Ther 6:1–15. https://doi.org/10.1186/alzrt272

    Article  CAS  Google Scholar 

  9. Reddy PH, Tripathi R, Troung Q et al (2012) Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta—Mol Basis Dis 1822:639–649. https://doi.org/10.1016/j.bbadis.2011.10.011

    Article  CAS  Google Scholar 

  10. Chaturvedi RK, Beal MF (2013) Mitochondrial diseases of the brain. Free Radic Biol Med 63:1–29. https://doi.org/10.1016/j.freeradbiomed.2013.03.018

    Article  CAS  PubMed  Google Scholar 

  11. Wallace DC (2013) Science in medicine A mitochondrial bioenergetic etiology of disease. J Clin Invest 123:1405–1412. https://doi.org/10.1172/JCI61398.across

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cardoso S, Carvalho C, Correia SC et al (2016) Alzheimer’s disease: from mitochondrial perturbations to mitochondrial medicine. Brain Pathol 26:632–647. https://doi.org/10.1111/bpa.12402

    Article  PubMed  Google Scholar 

  13. Cai Q, Tammineni P (2017) Mitochondrial aspects of synaptic dysfunction in Alzheimer’s disease. J Alzheimer’s Dis 57:1087–1103. https://doi.org/10.3233/JAD-160726

    Article  CAS  Google Scholar 

  14. Du H, Guo L, Fang F et al (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105. https://doi.org/10.1038/nm.1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dragicevic N, Copes N, O’Neal-Moffitt G et al (2011) Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling. J Pineal Res 51:75–86. https://doi.org/10.1111/j.1600-079X.2011.00864.x

    Article  CAS  PubMed  Google Scholar 

  16. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. https://doi.org/10.1126/science.1074069

    Article  CAS  PubMed  Google Scholar 

  17. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384. https://doi.org/10.1016/j.neurobiolaging.2005.09.012

    Article  CAS  PubMed  Google Scholar 

  18. Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharmacutical Des 16:2766–2778

    Article  CAS  Google Scholar 

  19. Itoh K, Chiba T, Takahashi S et al (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322. https://doi.org/10.1006/bbrc.1997.6943

    Article  CAS  PubMed  Google Scholar 

  20. Wilson AJ, Kerns JK, Callahan JF, Moody CJ (2013) Keap calm, and carry on covalently. J Med Chem 56:7463–7476. https://doi.org/10.1021/jm400224q

    Article  CAS  PubMed  Google Scholar 

  21. Ramsey CP, Glass CA, Montgomery MB et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85. https://doi.org/10.1097/nen.0b013e31802d6da9

    Article  CAS  Google Scholar 

  22. Joshi G, Gan KA, Johnson DA, Johnson JA (2015) Increased Alzheimer’s disease-like pathology in the APP/PS1δE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36:664–679. https://doi.org/10.1016/j.neurobiolaging.2014.09.004

    Article  CAS  PubMed  Google Scholar 

  23. Wright JW, Harding JW (2013) The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. Pflugers Arch Eur J Physiol 465:133–151. https://doi.org/10.1007/s00424-012-1102-2

    Article  CAS  Google Scholar 

  24. Miners JS, Ashby E, Baig S et al (2009) Angiotensin-converting enzyme levels and activity in Alzheimer’s disease: differences in brain and CSF ACE and association with ACE1 genotypes. Am J Transl Res 1:163–177

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wright JW, Harding JW (2010) The brain RAS and Alzheimer’s disease. Exp Neurol 223:326–333. https://doi.org/10.1016/j.expneurol.2009.09.012

    Article  CAS  PubMed  Google Scholar 

  26. Wright JW, Kawas LH, Harding JW (2013) A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Front Endocrinol (Lausanne) 4:1–12. https://doi.org/10.3389/fendo.2013.00158

    Article  CAS  Google Scholar 

  27. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19:1584–1596. https://doi.org/10.1038/nm.3407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meng Y, Yu CH, Li W et al (2014) Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway. Am J Respir Cell Mol Biol 50:723–736. https://doi.org/10.1165/rcmb.2012-0451OC

    Article  CAS  PubMed  Google Scholar 

  29. Xu P, Sriramula S, Lazartigues E (2011) ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good. Am J Physiol—Regul Integr Comp Physiol. https://doi.org/10.1152/ajpregu.00222.2010

    Article  PubMed  PubMed Central  Google Scholar 

  30. Jiang T, Gao L, Lu J et al (2013) ACE2-Ang-(1–7)-Mas axis in brain: a potential target for prevention and treatment of ischemic stroke. Curr Neuropharmacol 11:209–217. https://doi.org/10.2174/1570159x11311020007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Varshney V, Garabadu D (2021) Ang (1–7)/Mas receptor-axis activation promotes amyloid beta-induced altered mitochondrial bioenergetics in discrete brain regions of Alzheimer’s disease-like rats. Neuropeptides 9(86):102122. https://doi.org/10.1016/j.npep.2021.102122

    Article  CAS  Google Scholar 

  32. Chappell MC, Brosnihan KB, Diz DI et al (1989) Identification of angiotensin-(1–7) in rat brain. Evidence for differential processing of angiotensin peptides. J Biol Chem 264:16518–16523

    Article  CAS  Google Scholar 

  33. Lu W, Kang J, Hu K et al (2017) Angiotensin-(1–7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis. Braz J Med Biol Res 50:1–13. https://doi.org/10.1590/1414-431X20165594

    Article  Google Scholar 

  34. Romero A, San Hipólito-Luengo Á, Villalobos LA et al (2019) The angiotensin-(1–7)/Mas receptor axis protects from endothelial cell senescence via klotho and Nrf2 activation. Aging Cell 18:e12913. https://doi.org/10.1111/acel.12913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nakhate KT, Bharne AP, Verma VS et al (2018) Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer’s disease via activation of Nrf2/ARE pathway and inhibition of β-secretase. Biomed Pharmacother 101:379–390. https://doi.org/10.1016/j.biopha.2018.02.052

    Article  CAS  PubMed  Google Scholar 

  36. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, DC

    Google Scholar 

  37. Li X, Zhao X, Xu X et al (2014) Schisantherin A recovers Aβ-induced neurodegeneration with cognitive decline in mice. Physiol Behav 132:10–16. https://doi.org/10.1016/j.physbeh.2014.04.046

    Article  CAS  PubMed  Google Scholar 

  38. Lin HB, Yang XM, Li TJ et al (2009) Memory deficits and neurochemical changes induced by C-reactive protein in rats: Implication in Alzheimer’s disease. Psychopharmacology 204:705–714. https://doi.org/10.1007/s00213-009-1499-2

    Article  CAS  PubMed  Google Scholar 

  39. Chen X, Hu J, Jiang L et al (2014) Brilliant Blue G improves cognition in an animal model of Alzheimer’s disease and inhibits amyloid-β-induced loss of filopodia and dendrite spines in hippocampal neurons. Neuroscience 279:94–101. https://doi.org/10.1016/j.neuroscience.2014.08.036

    Article  CAS  PubMed  Google Scholar 

  40. Nillert N, Pannangrong W, Welbat JU et al (2017) Neuroprotective effects of aged garlic extract on cognitive dysfunction and neuroinflammation induced by β-amyloid in rats. Nutrients 9:1–13. https://doi.org/10.3390/nu9010024

    Article  CAS  Google Scholar 

  41. Pawlik MW, Kwiecien S, Ptak-Belowska A et al (2016) The renin-angiotensin system and its vasoactive metabolite angiotensin-(1–7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of mas receptors nitric oxide, prostaglandins and proinflammatory cytokines. J Physiol Pharmacol 67:75–91

    CAS  PubMed  Google Scholar 

  42. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Elsevier, Amsterdam

    Google Scholar 

  43. Muthuraju S, Maiti P, Solanki P et al (2009) Acetylcholinesterase inhibitors enhance cognitive functions in rats following hypobaric hypoxia. Behav Brain Res 203:1–14. https://doi.org/10.1016/j.bbr.2009.03.026

    Article  CAS  PubMed  Google Scholar 

  44. Pedersen PL, Greenawalt JW, Reynafarje B et al (1978) Preparation and characterization of mitochondria and submitochondrial particles of rat liver and liver-derived tissues. Methods Cell Biol 20:411–481. https://doi.org/10.1016/S0091-679X(08)62030-0

    Article  CAS  PubMed  Google Scholar 

  45. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275. https://doi.org/10.1016/0922-338X(96)89160-4

    Article  CAS  Google Scholar 

  46. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60. https://doi.org/10.1016/0165-0270(84)90007-4

    Article  CAS  Google Scholar 

  47. Mouri A, Noda Y, Hara H et al (2007) Oral vaccination with a viral vector containing Aβ cDNA attenuates age-related Aβ accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. FASEB J 21:2135–2148. https://doi.org/10.1096/fj.06-7685com

    Article  CAS  PubMed  Google Scholar 

  48. Zoukhri D, Kublin CL (2001) Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjögren’s syndrome. Investig Ophthalmol Visual Sci 42:925–932

    CAS  Google Scholar 

  49. Kamboj SS, Kumar V, Kamboj A, Sandhir R (2008) Mitochondrial oxidative stress and dysfunction in rat brain induced by carbofuran exposure. Cell Mol Neurobiol 28:961–969. https://doi.org/10.1007/s10571-008-9270-5

    Article  CAS  PubMed  Google Scholar 

  50. Huang S-G (2002) Development of a high throughput screening assay for mitochondrial membrane potential in living cells. J Biomol Screen 7:383–389. https://doi.org/10.1177/108705710200700411

    Article  CAS  PubMed  Google Scholar 

  51. Chance B, Williams GR (1956) Respiratory enzymes in oxidative phosphorylation. VI. The effects of adenosine diphosphate on azide-treated mitochondria. J Biol Chem 221:477–489

    Article  CAS  Google Scholar 

  52. Liu D, Xiao B, Han F et al (2012) Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of posttraumatic stress disorder. BMC Psychiatry 12:1. https://doi.org/10.1186/1471-244X-12-211

    Article  CAS  Google Scholar 

  53. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. https://doi.org/10.1006/abio.1976.9999

    Article  CAS  Google Scholar 

  54. Lazaroni TLN, Raslan ACS, Fontes WRP et al (2012) Angiotensin-(1–7)/Mas axis integrity is required for the expression of object recognition memory. Neurobiol Learn Mem 97:113–123. https://doi.org/10.1016/j.nlm.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  55. Chen JL, Zhang DL, Sun Y et al (2017) Angiotensin-(1–7) administration attenuates Alzheimer’s disease-like neuropathology in rats with streptozotocin-induced diabetes via Mas receptor activation. Neuroscience 346:267–277. https://doi.org/10.1016/j.neuroscience.2017.01.027

    Article  CAS  PubMed  Google Scholar 

  56. Kamel AS, Abdelkader NF, Abd El-Rahman SS et al (2018) Stimulation of ACE2/ANG(1–7)/Mas axis by diminazene ameliorates Alzheimer’s disease in the D-galactose-ovariectomized rat model: role of PI3K/Akt pathway. Mol Neurobiol 55:8188–8202. https://doi.org/10.1007/s12035-018-0966-3

    Article  CAS  PubMed  Google Scholar 

  57. Bevilaqua ER, Kushmerick C, Beirão PS et al (2002) Angiotensin 1–7 increases quantal content and facilitation at the frog neuromuscular junction. Brain Res 927:208–211. https://doi.org/10.1016/s0006-8993(01)03357

    Article  PubMed  Google Scholar 

  58. Bowen DM, Smith CB, White P, Davison AN (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99:459–496. https://doi.org/10.1093/brain/99.3.459

    Article  CAS  PubMed  Google Scholar 

  59. Whitehouse PJ, Price DL, Clark AW et al (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126. https://doi.org/10.1002/ana.410100203

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

VV is thankful to GLA University, Mathura, Uttar Pradesh, India for the financial support.

Author information

Authors and Affiliations

  1. Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India

    Vibhav Varshney & Debapriya Garabadu

Authors
  1. Vibhav Varshney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debapriya Garabadu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Debapriya Garabadu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1072 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Varshney, V., Garabadu, D. Ang(1–7) exerts Nrf2-mediated neuroprotection against amyloid beta-induced cognitive deficits in rodents. Mol Biol Rep 48, 4319–4331 (2021). https://doi.org/10.1007/s11033-021-06447-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06447-1

Keywords

Search

Navigation