Changes in the transcriptome of the prefrontal cortex of OXYS rats as the signs of Alzheimer’s disease development. N. A. Stefanova, E. E. Korbolina, N. I. Ershov, E. I. Rogaev, N. G. Kolosova ВАВИЛОВСКИЙ

Abstract:

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. It produces atrophic changes in the brain, which cause dementia. The incidence of AD is increasing with increasing life expectancy and gradual aging of the population in developed countries. There are no effective prophylactic interventions because of insufficient understanding of the AD pathogenesis and the absence of adequate experimental models. Recently, we showed that senescence-accelerated OXYS rats represent a promising model of AD; in these rats, accelerated aging of the brain is accompanied by the typical signs of AD: degenerative alterations and death of neurons, a decrease in synaptic density, mitochondrial dysfunction, hyperphosphorylation of the tau protein, an increased level of amyloid β (Aβ1–42), and the formation of amyloid plaques. To elucidate how these signs develop, we used a nextgeneration RNA sequencing technique (RNA-Seq) to study the prefrontal-cortex transcriptome of OXYS rats during the manifestation of AD signs (at an age of 5 months) and during their active progression (at an age of 18 months), using age-matched Wistar rats (parental strain) as controls. At the age of 5 months, there were significant differences between OXYS and Wistar rats (p < 0.01) in the mRNA expression of more than 900 genes (> 2000 genes at the age of 18 months) in the prefrontal cortex. Most of these genes were related to neuronal plasticity, protein phosphorylation, Са2+ homeostasis, hypoxia, immune processes, and apoptosis. Between the ages of 5 and 18 months, there were changes in the expression of 499 genes in Wistar rats and changes in the expression of 5500 genes in OXYS rats. Only 333 genes were common between these sets. This finding points to differences in the mechanisms and rates of age-related changes in the brain between normal aging and the period of development of AD-specific neurodegenerative processes.

About The Authors:

N. A. Stefanova. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

E. E. Korbolina. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

N. I. Ershov. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

E. I. Rogaev. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

N. G. Kolosova. Institute of Cytology and Genetics SB RAS; Novosibirsk State University, Russian Federation, Novosibirsk

References:

1. Anders S., Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11(10):R106. DOI: 10.1186/gb-2010-11-10-r106

2. Beregovoy N.A., Sorokina N.S., Starostina M.V., Kolosova N.G. Age-specific peculiarities of formation of long-term posttetanic potentiation in OXYS rats. Byulleten eksperimentalnoi biologii i meditsiny — Bulletin of Experimental Biology and Medicine. 2011; 151(1):82-86.

3. Bertram L., McQueen M.B., Mullin K., Blacker D., Tanzi R.E. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 2007;39(1):17-23.

4. Cho J.H., Johnson G.V. Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ. J. Biol. Chem. 2004;279(52): 54716-54723.

5. Chung C.W., Song Y.H., Kim I.K., Yoon W.J., Ryu B.R., Jo D.G., Woo H.N., Kwon Y.K., Kim H.H., Gwag B.J., Mook-Jung I.H., Jung Y.K. Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol Dis. 2001;8(1):162-172.

6. Kanemitsu H., Tomiyama T., Mori H. Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci Lett. 2003;350(2):113-116.

7. Kolosova N.G., Akulov A.E., Stefanova N.A., Moshkin M.P., Savelov A.A., Koptyug I.V., Panov A.V., Vavilin V.A. Effect of malate on the development of rotenone-induced brain changes in Wistar and OXYS rats: An MRI study. Doklady AN — Doklady Biological Sciences. 2011;437(2):273-276.

8. Kolosova N.G., Stefanova N.A., Korbolina E.E., Fursova A.Zh., Kozhevnikova O.S. The senescence-accelerated OXYS rats — a genetic model of premature aging and age-dependent degenerative diseases. Uspekhi gerontologii Rossiiskaia akademiia nauk, Gerontologicheskoe obshchestvo) — Advances in gerontology. 2014;27(2):336-340.

9. Kolosova N.G., Stefanova N.A., Sergeeva S.V. OXYS rats: a prospective model for evaluation of antioxidant availability in prevention and therapy of accelerated aging and age-related cognitive decline. Eds Q. Gariépy, R. Ménard. Handbook of Cognitive Aging: Causes, Processes. N.Y.: Nova Sci. Publ., 2009.

10. Korbolina E.E., Kozhevnikova O.S., Stefanova N.A., Kolosova N.G. Quantitative trait loci on chromosome 1 for cataract and AMD-like retinopathy in senescence-accelerated OXYS rats. Aging (Albany NY). 2012;4(1):49-59.

11. Kozhevnikova O.S., Korbolina E.E., Ershov N.I., Kolosova N.G. Rat retinal transcriptome: effects of aging and AMD-like retinopathy. Cell Cycle. 2013;12(11):1745-1761. DOI: 10.4161/cc.24825

12. Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 2013;9(1):25-34. DOI: 10.1038/nrneurol.2012.236

13. Maeda N., Ishii M., Nishimura K., Kamimura K. Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem. Res. 2011;36(7):1228-1240. DOI: 10.1007/s11064-010-0324-y

14. Markova E.V., Obukhova L.A., Kolosova N.G. Parameters of cell immune response in Wistar and OXYS rats and their behavior in the open field test. Bul. Exp. Biol. Med. 2003;136(6):588-590.

15. Mawuenyega K.G., Sigurdson W., Ovod V., Munsell L., Kasten T., Morris J.C., Yarasheski K.E., Bateman R.J. Decreased slearance of CNS beta-Amyloid in Alzheimer’s disease. Science. 2010;330(6012): 1774. DOI:10.1126/science.1197623

16. Morley J.E., Armbrecht H.J., Farr S.A., Kumar V.B. The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease. Biochim. Biophys Acta. 2012;1822(5):650-656. DOI:10.1016/j.bbadis.2011.11.015

17. Obukhova L.A., Skulachev V.P., Kolosova N.G. Mitochondria-targeted antioxidant SkQ1 inhibits age-dependent involution of the thymus in normal and senescence-prone rats. Aging (Albany N.Y.). 2009;1(4):389-401.

18. Rykova V.I., Leberfarb E.Y., Stefanova N.A., Shevelev O.B., Dymshits G.M., Kolosova N.G. Brain proteoglycans in postnatal development and during behavior decline in senescence-accelerated OXYS rats. Adv. Gerontol. 2011;24(2):234-243.

19. Querfurth H.W., LaFerla F.M. Alzheimer’s disease. N. Engl. J. Med. 2010;362(4):329-344. DOI:10.1056/NEJMra0909142

20. Scheff S.W., Neltner J.H., Nelson P.T. Is synaptic loss a unique hallmark of Alzheimer’s disease? Biochem. Pharmacol. 2014;88(4):517-528. DOI: 10.1016/j.bcp.2013.12.028

21. Shevelev O.B., Rykova V.I., Fedoseeva L.A., Leberfarb E.Y., Dymshits G.M., Kolosova N.G. Expression of Ext1, Ext2, and heparanase genes in brain of senescence-accelerated OXYS rats in early ontogenesis and during development of neurodegenerative changes. Biokhimiya — Biochemistry (Moscow). 2012;77(1):56-61.

22. Shinohara M., Fujioka S., Murray M.E., Wojtas A., Baker M., RoveletLecrux A., Rademakers R., Das P., Parisi J.E., Graff-Radford N.R., Petersen R.C., Dickson D.W., Bu G. Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain. 2014;137(Pt 5): 1533-1549. DOI: 10.1093/brain/awu046

23. Stefanova N.A., Fursova A., Kolosova N.G. Behavioral effects induced by mitochondria-targeted antioxidant SkQ1 in Wistar and senescence-accelerated OXYS rats. J. Alzheimers Dis. 2010;21(2): 479-491. DOI: 10.3233/JAD-2010-091675

24. Stefanova N.A., Kozhevnikova O.S., Vitovtov A.O., Maksimova K.Y., Logvinov S.V., Rudnitskaya E.A., Korbolina E.E., Muraleva N.A., Kolosova N.G. Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease. Cell Cycle. 2014a;13(6):898-909. DOI: 10.4161/cc.28255

25. Stefanova N.A., Maksimova K.Y., Kiseleva E., Rudnitskaya E.A., Muraleva N.A., Kolosova N.G. Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer’s disease-like pathology. J. Pineal Res. 2015b;59(2):163-177. DOI: 10.1111/jpi.12248

26. Stefanova N.A., Muraleva N.A., Korbolina E.E., Kiseleva E., Maksimova K.Y., Kolosova N.G. Amyloid accumulation is a late event in sporadic Alzheimer’s disease-like pathology in nontransgenic rats. Oncotarget. 2015a;6(3):1396-1413.

27. Stefanova N.A., Muraleva N.A., Skulachev V.P., Kolosova N.G. Alzheimer’s disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1. J. Alzheimers Dis. 2014b;38(3):681-694. DOI: 10.3233/JAD-131034

28. Trapnell C., Pachter L., Salzberg S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009;25(9):1105-1111. DOI: 10.1093/bioinformatics/btp120

29. Winkler J.M., Fox H.S. Transcriptome meta-analysis reveals a central role for sex steroids in the degeneration of hippocampal neurons in Alzheimer’s disease. BMC Syst. Biol. 2013;7:51. DOI:10.1186/1752-0509-7-51