Mechanisms of the spatial memory deficits induced by injection of okadaic acid into the Meynert nucleus basalis of rats

Abstract

We previously reported that the injection of okadaic acid (OA) into the Meynert nucleus basalis of rats induced spatial memory deficits. The present study was designed to further explore the underlying mechanisms. We found that the level of acetylcholine (Ach) in the hippocampus significantly decreased 24 h after injection of OA into the Meynert nucleus basalis of rats. Simultaneously, spatial memory deficit, PP-2A inhibition and tau hyperphosphorylation at Ser-198/Ser-199/Ser-202 (Tau-1 epitope) and Ser-396/Ser-404 (PHF-1 epitope) were observed. With the restoration of hippocampus Ach to normal levels at 48 and 72 h after the injection, the spatial memory deficits, PP-2A inhibition and tau hyperphosphorylation were reversed. It is suggested that injection of OA into the Meynert nucleus basalis of rats may impair the hippocampus-dependent spatial memory through damaging the cholinergic projection between the Meynert nucleus basalis and the hippocampus and the selective inhibition of PP-2A and tau hyperphosphorylation may be at least part of the underlying mechanisms.

References

1. Arriagada P V Growdon J H Hedley-Whyte E T Hyman B T Neurofibrillarytangles but not senile plaques parallel duration and severity of Alzheimer'sdiseaseNeurology 1992 42(3Pt1)631639
2. Alonso A C Zaidi T Novak M Grundke-Iqbal I Iqbal K Hyperphosphorylation inducesself-assembly of τ into tangles of paired helical filaments/straightfilamentsProc Natl Acad Sci USA 2001 98(12)69236928. doi:10.1073/pnas.121119298
3. Tian Q Wang J Z Role of serine/theonine proteinphosphatase in Alzheimer's diseaseNeurosignals 2002 11(5)262269. doi:10.1159/000067425
4. Gong C X Singh T J Grundke-Iqbal I Iqbal K Phosphoproteinphosphatase activities in Alzheimer disease brainJ Neurochem 1993 61(3)921927. doi:10.1111/j.1471‐4159.1993.tb03603.x
5. Gong C X Shaikh S Wang J Z Zaidi T Grundke-Iqbal I Iqbal K Phosphatase activity toward abnormally phosphorylated tau:decrease in Alzheimer disease brainJ Neurochem 1995 65(2)732738
6. Vogelsberg-Ragaglia V Schuck T Trojanowski J Q Lee V M PP2A mRNA expressionis quantitatively decreased in Alzheimer's disease hippocampusExp Neurol 2001 168(2)402412. doi:10.1006/exnr.2001.7630
7. Sontag E Nunbhakdi-Craig V Lee G Bloom G S Mumby M C Regulation of the phosphorylation stateand microtubule-binding activity of Tau by protein phosphatase 2ANeuron 1996 17(6)12011207. doi:10.1016/S0896‐6273(00)80250‐0
8. Kim D Su J Cotman C W Sequence of neurodegeneration and accumulation of phosphorylatedtau in cultured neurons after okadaic acid treatmentBrain Res 1999 839(2)253262. doi:10.1016/S0006‐8993(99)01724‐2
9. Gong C X Lidsky T Wegiel J Zuck L Grundke-Iqbal I Iqbal K Phosphorylation of microtubule-associated protein tau isregulated by protein phosphatase 2A in mammalian brain. Implicationsfor neurofibrillary degeneration in Alzheimer's diseaseJ Biol Chem 2000 275(8)55355544. doi:10.1074/jbc.275.8.5535
10. Sun L Liu S Y Wang J Z Inhibition of PP2A and PP1 induced tau hyperphosphorylationand impairment of spatial memory retention in ratsNeuroscience 2003 118(4)11751182. doi:10.1016/S0306‐4522(02)00697‐8
11. Whitehouse P J Price D L Struble R G Clark A W Coyle J T DeLong M R Alzheimer'sdisease and senile dementia: loss of neurons in the basal forebrainScience 1982 215(4537)12371239. doi:10.1126/science.7058341
12. Coyle J T Price D L DeLong M R Alzheimer's disease: a disorder of cortical cholinergicinnervationScience 1983 219(4589)11841190. doi:10.1126/science.6338589
13. Rasool C G Svendsen C N Selkoe D J Neurofibrillary degeneration of cholinergic and noncholinergicneurons of the basal forebrain in Alzheimer's diseaseAnn Neurol 1986 20(4)482488. doi:10.1002/ana.410200407
14. Samuel W Terry R D DeTeresa R Butters N Masliah E Clinical correlates of cortical and nucleusbasalis pathology in Alzheimer dementiaArch Neurol 1994 51(8)772778
15. Tian Q Lin Z Q Wang X C Chen J Wang Q Gong C X Wang J Z Injection of okadaic acid intothe Meynert nucleus basalis of rat brain induces decreased acetylcholinelevel and spatial memory deficitNeuroscience 2004 126(2)277284. doi:10.1016/j.neuroscience.2004.03.037
16. Brandeis R Brandys Y Yehuda S The use of the Morris water maze in the study of memoryand learningInt J Neurosci 1989 48(1–2)2969
17. Paxinos G Watson C J The Rat Brain in StereotaxicCoordinates 1996 2nd Edition Academic PressNew York
18. Gong C X Singh T J Grundke-Iqbal I Iqbal K Alzheimer's diseaseabnormally phosphorylated tau is dephosphorylated by protein phosphatase-2B(calcineurin)J Neurochem 1994 62(2)803806
19. Zhang C E Tian Q Wei W Pen J H Liu G P Zhou X W Wang Q Wang D W Wang J Z Homocysteineinduces tau phosphorylation by inactivating protein phosphatase 2Ain rat hippocampusNeurobiol Aging 2007 [Epub ahead of print]
20. Bialojan C Takai A Inhibitory effect of a marine-spongetoxin, okadaic acid, on protein phosphatases, Specificity and kineticsBiochem J 1988 256(1)283290
21. Sarter M Bruno J P Cortical cholinergic inputsmediating arousal, attentional processing and dreaming: differentialafferent regulation of the basal forebrain by telencephalic and brainstemafferentsNeuroscience 2000 95(4)933952. doi:10.1016/S0306‐4522(99)00487‐X
22. Semba K Multipleoutput pathways of the basal forebrain: organization, chemical heterogeneity,and roles in vigilanceBehav Brain Res 2000 115(2)117141. doi:10.1016/S0166‐4328(00)00254‐0
23. Szymusiak R Alam N McGinty D Discharge patterns of neurons in cholinergic regions ofthe basal forebrain during waking and sleepBehav Brain Res 2000 115(2)171182. doi:10.1016/S0166‐4328(00)00257‐6
24. Mesulam M M Thesystems-level organization of cholinergic innervation in the humancerebral cortex and its alterations in Alzheimer's diseaseProg Brain Res 1996 109285297
25. Imperato A Dazzi L Obinu M C Gessa G L Biggio G Inhibition of hippocampal acetylcholinerelease by benzodiazepines: antagonism by flumazenil.Eur J Pharmacol 1993 238(1)135137
26. Issa A M Gauthier S Collier B Effects of the phosphatase inhibitors calyculin A and okadaicacid on acetylcholine synthesis and content of rat hippocampal formationJ Neurochem 1996 66(5)19241932
27. Gong C X Wang J Z Iqbal K Grundke-Iqbal I Inhibitionof protein phosphatase 2A induces phosphorylation and accumulationof neurofilaments in metabolically active rat brain slicesNeurosci Lett 2003 340(2)107110. doi:10.1016/S0304‐3940(03)00096‐X
28. Wang J Z Tung Y C Wang Y Li X T Iqbal K Grundke-Iqbal I Hyperphosphorylationand accumulation of neurofilament proteins in Alzheimer disease brainand in okadaic acid-treated SY5Y cellsFEBSLett 2001 507(1)8187. doi:10.1016/S0014‐5793(01)02944‐1
29. Wang L Y Diao L M Tian Q Wang J Z Gong C X Protein phosphatase 2A regulatesphosphorylationof microtubule-associated protein 1bShengWu Hua Xue Yu Sheng Wu Wu Li Jin Zhan 2004 31(11)986990(in Chinese)