SpringerLink
Log in

Okadaic Acid and Hypoxia Induced Dementia Model of Alzheimer’s Type in Rats

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism and progression, animal models for the specific disease are needed. For AD, although highly valid animal models exist, none of the existing models recapitulates all aspects of human AD. The pathogenic mechanisms involved in AD are diverse and thus it is difficult to recapitulate human AD in model organisms. Intracerebroventricular (ICV) injection of okadaic acid (OKA), a protein phosphatase 2A (PP2A) inhibitor, in rats causes neurotoxicity associated with neurofibrillary degeneration. However, this model lacks amyloid pathology as observed in AD. We aimed at combining two different treatments and hence producing a better animal model of AD which may mimic most of the neuropathological, neurobehavioral, and neurochemical changes observed in AD. For this, OKA (200 ng) was microinjected bilaterally into the hippocampus of male Wistar rats followed by exposure of same rats to hypoxic conditions (10%) for 3 days. The result of which, the combination model exhibited tau hyperphosphorylation along with Aβ upregulation as evident by western blotting and immunohistochemistry. The observed changes were accompanied with dysfunction of neurotransmitter system, i.e., decreased acetylcholine activity and expression. This combinatorial model also exhibited cognitive deficiency which was assessed by Morris water maze and avoidance tests along with enhanced oxidative stress which is thought to be a major player in AD pathogenesis. Taken together, we established an easily reproducible and reliable rat model for sporadic dementia of Alzheimer’s type in rats which allows effective testing of new therapeutic strategies.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

Abbreviations

Aβ:

Beta amyloid

NFTs:

Neurofibrillary tangles

OKA:

Okadaic acid

ROS:

Reactive oxygen species

PHF:

Paired helical filament

H2-DCFHDA:

2′,7′-Dichlorodihydrofluorescein diacetate

SOD:

Superoxide dismutase

References

  • Alzheimer’s Association (2015) 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 11:332–384

    Article  Google Scholar 

  • Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12:459–509

    Article  Google Scholar 

  • Anand R, Kaushal A, Wani WY, Gill KD (2012) Road to Alzheimer’s disease: the pathomechanism underlying. Pathobiology 79:55–71

    Article  PubMed  CAS  Google Scholar 

  • Areosa SA, Sherriff F (2003) Memantine for dementia Cochrane Database Syst Rev:CD003154

  • Braak H, Braak E (1996) Evolution of the neuropathology of Alzheimer’s disease. Acta Neurol Scand Suppl 165:3–12

    Article  PubMed  CAS  Google Scholar 

  • Broetto N, Hansen F, Brolese G, Batassini C, Lirio F, Galland F, dos Santos JPA, Dutra MF, Gonçalves CA (2016) Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation. Brain Res Bull 124:136–143

    Article  PubMed  CAS  Google Scholar 

  • Bromley-Brits K, Deng Y, Song W (2011) Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp 20:2920

    Google Scholar 

  • Chavez JC, Agani F, Pichiule P, LaManna JC (2000) Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia. J Appl Physiol (1985) 89:1937–1942

    Article  CAS  Google Scholar 

  • Choi PM, Zelig MP (1994) Similarity of colorectal cancer in Crohn’s disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 35:950–954

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cotman CW, Su JH (1996) Mechanisms of neuronal death in Alzheimer’s disease. Brain Pathol 6:493–506

    Article  PubMed  CAS  Google Scholar 

  • Dimitrova DS, Getova-Spassova DP (2006) Effects of galantamine and donepezil on active and passive avoidance tests in rats with induced hypoxia. J Pharmacol Sci 101:199–204

    Article  PubMed  CAS  Google Scholar 

  • Dwivedi S, Nagarajan R, Hanif K, Siddiqui HH, Nath C, Shukla R (2013) Standardized extract of Bacopa monniera attenuates okadaic acid induced memory dysfunction in rats: effect on Nrf2 pathway. Evid Based Complement Alternat Med 2013:294501

    Article  PubMed  PubMed Central  Google Scholar 

  • Forny-Germano L, Lyra e Silva NM, Batista AF, Brito-Moreira J, Gralle M, Boehnke SE, Coe BC, Lablans A, Marques SA, Martinez AMB, Klein WL, Houzel JC, Ferreira ST, Munoz DP, de Felice FG (2014) Alzheimer’s disease-like pathology induced by amyloid-beta oligomers in nonhuman primates. J Neurosci 34:13629–13643

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gao L, Tian S, Gao H, Xu Y (2013) Hypoxia increases Abeta-induced tau phosphorylation by calpain and promotes behavioral consequences in AD transgenic mice. J Mol Neurosci 51:138–147

    Article  PubMed  CAS  Google Scholar 

  • Glowinski J, Iversen L (1966) Regional studies of catecholamines in the rat brain. 3. Subcellullar distribution of endogenous and exogenous catecholamines in various brain regions. Biochem Pharmacol 15:977–987

    Article  PubMed  CAS  Google Scholar 

  • Gordon RY, Mugantseva EA, Khutzian SS, Podolski IY (2009) Cycloheximide-induced inhibition of protein synthesis in hippocampal pyramidal neurons is time-dependent: differences between CA1 and CA3 areas. Neurosci Lett 461:249–251

    Article  PubMed  CAS  Google Scholar 

  • Honig LS, Tang MX, Albert S, Costa R, Luchsinger J, Manly J, Stern Y, Mayeux R (2003) Stroke and the risk of Alzheimer disease. Arch Neurol 60:1707–1712

    Article  PubMed  Google Scholar 

  • Kamat PK, Rai S, Nath C (2013a) Okadaic acid induced neurotoxicity: an emerging tool to study Alzheimer's disease pathology. Neurotoxicology 37:163–172

    Article  PubMed  CAS  Google Scholar 

  • Kamat PK, Rai S, Swarnkar S, Shukla R, Ali S, Najmi AK, Nath C (2013b) Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor. Neuroscience 238:97–113

    Article  PubMed  CAS  Google Scholar 

  • Kamat PK, Rai S, Swarnkar S, Shukla R, Nath C (2014) Molecular and cellular mechanism of okadaic acid (OKA)-induced neurotoxicity: a novel tool for Alzheimer’s disease therapeutic application. Mol Neurobiol 50:852–865

    Article  PubMed  CAS  Google Scholar 

  • Kar S, Slowikowski SPM, Westaway D, Mount HTJ (2004) Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci 29:427–441

    PubMed  PubMed Central  Google Scholar 

  • Ladner CJ, Lee JM (1998) Pharmacological drug treatment of Alzheimer disease: the cholinergic hypothesis revisited. J Neuropathol Exp Neurol 57:719–731

    Article  PubMed  CAS  Google Scholar 

  • Lecanu L, Greeson J, Papadopoulos V (2006) Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis, and memory impairment in the rat brain. Pharmacology 76:19–33

    Article  PubMed  CAS  Google Scholar 

  • Maddahi A, Edvinsson L (2008) Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway. BMC Neurosci 9:85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, Freedman ML (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 150:40–44

    Article  PubMed  CAS  Google Scholar 

  • Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751

    Article  PubMed  CAS  Google Scholar 

  • Melov S (2002) Animal models of oxidative stress, aging, and therapeutic antioxidant interventions. Int J Biochem Cell Biol 34:1395–1400

    Article  PubMed  CAS  Google Scholar 

  • Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  PubMed  CAS  Google Scholar 

  • Muir JL, Page KJ, Sirinathsinghji DJ, Robbins TW, Everitt BJ (1993) Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention. Behav Brain Res 57:123–131

    Article  PubMed  CAS  Google Scholar 

  • Nakamura S, Murayama N, Noshita T, Annoura H, Ohno T (2001) Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide. Brain Res 912:128–136

    Article  PubMed  CAS  Google Scholar 

  • Ng KM, Lau CF, Fung ML (2010) Melatonin reduces hippocampal beta-amyloid generation in rats exposed to chronic intermittent hypoxia. Brain Res 1354:163–171

    Article  PubMed  CAS  Google Scholar 

  • Ogunshola OO, Antoniou X (2009) Contribution of hypoxia to Alzheimer’s disease: is HIF-1alpha a mediator of neurodegeneration? Cell Mol Life Sci 66:3555–3563

    Article  PubMed  CAS  Google Scholar 

  • Olanow CW (1993) A radical hypothesis for neurodegeneration. Trends Neurosci 16:439–444

    Article  PubMed  CAS  Google Scholar 

  • Palmer AM, Burns MA (1994) Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer’s disease. Brain Res 645:338–342

    Article  PubMed  CAS  Google Scholar 

  • Partridge RS, Monroe SM, Parks JK, Johnson K, Parker WD Jr, Eaton GR, Eaton SS (1994) Spin trap** of azidyl and hydroxyl radicals in azide-inhibited rat brain submitochondrial particles. Arch Biochem Biophys 310:210–217

    Article  PubMed  CAS  Google Scholar 

  • Piala JJ, High JP, Hassert GL Jr, Burke JC, Craver BN (1959) Pharmacological and acute toxicological comparisons of triflupromazine and chlorpromazine. J Pharmacol Exp Ther 127:55–65

    PubMed  CAS  Google Scholar 

  • Pichiule P, LaManna JC (2002) Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia. J Appl Physiol (1985) 93:1131–1139

    Article  CAS  Google Scholar 

  • Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA (2000) Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 48:809–812

    Article  PubMed  CAS  Google Scholar 

  • Price DL, Sisodia SS (1998) Mutant genes in familial Alzheimer’s disease and transgenic models. Annu Rev Neurosci 21:479–505

    Article  PubMed  CAS  Google Scholar 

  • Reist M, Marshall KA, Jenner P, Halliwell B (1998) Toxic effects of sulphite in combination with peroxynitrite on neuronal cells. J Neurochem 71:2431–2438

    Article  PubMed  CAS  Google Scholar 

  • Richer MJ, Lavallee DJ, Shanina I, Horwitz MS (2009) Toll-like receptor 3 signaling on macrophages is required for survival following coxsackievirus B4 infection. PLoS One 4:e4127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sharma DR, Sunkaria A, Bal A, Bhutia YD, Vijayaraghavan R, Flora SJ, Gill KD (2009) Neurobehavioral impairments, generation of oxidative stress and release of pro-apoptotic factors after chronic exposure to sulphur mustard in mouse brain. Toxicol Appl Pharmacol 240:208–218

    Article  PubMed  CAS  Google Scholar 

  • Snyder B, Shell B, Cunningham JT, Cunningham RL (2017) Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early-stage neurodegeneration. Physiol Rep 5(9):e13258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99:195–231

    Article  PubMed  CAS  Google Scholar 

  • Sriram K, Pai KS, Boyd MR, Ravindranath V (1997) Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res 749:44–52

    Article  PubMed  CAS  Google Scholar 

  • Udayabanu M, Kumaran D, Nair RU, Srinivas P, Bhagat N, Aneja R, Katyal A (2008) Nitric oxide associated with iNOS expression inhibits acetylcholinesterase activity and induces memory impairment during acute hypobaric hypoxia. Brain Res 1230:138–149

    Article  PubMed  CAS  Google Scholar 

  • Unkruer B et al (2009) Cellular localization of Y-box binding protein 1 in brain tissue of rats, macaques, and humans. BMC Neurosci 10:28

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wasilewski M, Wojtczak L (2005) Effects of N-acylethanolamines on the respiratory chain and production of reactive oxygen species in heart mitochondria. FEBS Lett 579:4724–4728

    Article  PubMed  CAS  Google Scholar 

  • Watson C, Paxinos G (2007) The rat brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  • Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99:667–676

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang X, Le W (2010) Pathological role of hypoxia in Alzheimer’s disease. Exp Neurol 223:299–303

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Simpkins JW (2010) Okadaic acid induces tau phosphorylation in SH-SY5Y cells in an estrogen-preventable manner. Brain Res 1345:176–181

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang QG, Wang R, Khan M, Mahesh V, Brann DW (2008) Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci 28:8430–8441

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This study was funded by Council of Scientific and Industrial Research (CSIR).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Alka Kaushal, Willayat Yousuf Wani, Kiran Dip Gill & Jyotdeep Kaur

  2. The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Ward 12-369, Chicago, IL, 60611, USA

    Willayat Yousuf Wani

  3. Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Amanjit Bal

Authors
  1. Alka Kaushal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Willayat Yousuf Wani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amanjit Bal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kiran Dip Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jyotdeep Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jyotdeep Kaur.

Ethics declarations

Conflict of Interest

No conflicts of interest are declared by the authors.

Additional information

Publisher’s Note

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

Highlights

• Okadaic acid and hypoxia induce plaque and tangle pathology in this rat model of AD

• Combination of okadaic acid and hypoxia produced enhanced oxidative stress and associated neurodegeneration in rat brain

• Okadaic acid and hypoxia exposure to rats mimic the neurobehavioral and neurochemical alterations as observed in AD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaushal, A., Wani, W.Y., Bal, A. et al. Okadaic Acid and Hypoxia Induced Dementia Model of Alzheimer’s Type in Rats. Neurotox Res 35, 621–634 (2019). https://doi.org/10.1007/s12640-019-0005-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-019-0005-9

Keywords

Search

Navigation