Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Abstract

Neurotrophins are established molecular mediators of neuronal plasticity in the adult brain. We analyzed the impact of aging on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein isoforms, their receptors, and on the expression patterns of multiple 5′ exon-specific BDNF transcripts in the rat cortex and hippocampus throughout the life span of the rat (6, 12, 18, and 24 months of age). ProNGF was increased during aging in both structures. Mature NGF gradually decreased in the cortex, and, in 24-month-old animals, it was 30 % lower than that in adult 6-month-old rats. The BDNF expression did not change during aging, while proBDNF accumulated in the hippocampus of aged rats. Hippocampal total BDNF mRNA was lower in 12-month-old animals, mostly as a result of a decrease of BDNF transcripts 1 and 2. In contrast to the region-specific regulation of specific exon-containing BDNF mRNAs in adult animals, the same BDNF RNA isoforms (containing exons III, IV, or VI) were present in both brain structures of aged animals. Deficits in neurotrophin signaling were supported by the observed decrease in Trk receptor expression which was accompanied by lower levels of the two main downstream effector kinases, pAkt and protein kinase C. The proteolytic processing of p75NTR observed in 12-month-old rats points to an additional regulatory mechanism in early aging. The changes described herein could contribute to reduced brain plasticity underlying the age-dependent decline in cognitive function.

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

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

References

  1. Aid T, Kazantseva A, Piirsoo M, Palm, Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisted. J Neurosci Res 85:525–535

  2. Baj G, Leone E, Chao MV, Tongiorgi E (2011) Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments. Proc Natl Acad Sci USA 108:16813–16818

  3. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535

  4. Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125

  5. Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40

  6. Cacquevel M, Launay S, Castel H, Benchenane K, Chéenne S, Buée L, Moons L, Delacourte A, Carmeliet P, Vivien D (2007) Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms. Neurobiol Dis 27:164–173

  7. Chapman TR, Barrientos RM, Ahrendsen JT, Hoover JM, Maier SF, Patterson SL (2012) Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol Aging 33:832.e1–14

  8. Chiaruttini C, Sonego M, Baj G, Simonato M, Tongiorgi E (2008) BDNF mRNA splice variants display activity-dependent targeting to distinct hippocampal laminae. Mol Cell Neurosci 37:11–19

  9. Croll SD, Ip NY, Lindsay RM, Wiegand SJ (1998) Expression of BDNF and trkB as a function of age and cognitive performance. Brain Res 812:200–208

  10. Del Arco A, Segovia G, de Blas M, Garrido P, Acuña-Castroviejo D, Pamplona R, Mora F (2011) Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory. Behav Brain Res 216:136–145

  11. Fahnestock M, Michalski B, Xu B, Coughlin MD (2001) The precursor pro-nerve growth factor is the predominant formof nerve growth factor in brain and is increased in Alzheimer’s disease. Mol Cell Neurosci 18:210–220

  12. Fahnestock M, Yu G, Michalski B, Mathew S, Colquhoun A, Ross GM, Coughlin MD (2004) The nerve growth factor precursor proNGF exhibits neurotrophic activity but is less active than mature nerve growth factor. Neurochem 89:581–592

  13. Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29:12764–12767

  14. Hara D, Miyashita T, Fukuchi M, Suzuki H, Azuma Y, Tabuchi A, Tsuda M (2009) Persistent BDNF exon I-IX mRNA expression following the withdrawal of neuronal activity in neurons. Biochem Biophys Res Commun 390:648–653

  15. Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57:846–851

  16. Kelly A, Maguire C, Lynch MA (2000) Deficits in nerve growth factor release and tyrosine receptor kinase phosphorylation are associated with age-related impairment in long-term potentiation in the dentate gyrus. Neuroscience 95(2):359–365

  17. Kokaia Z, Metsis M, Kokaia M, Bengzon J, Elmér E, Smith ML, Timmusk T, Siesjö BK, Persson H, Lindvall O (1994) Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters. Eur J Neurosci 6:587–596

  18. Kokaia Z, Andsberg G, Yan Q, Lindvall O (1998) Rapid alterations of BDNF protein levels in the rat brain after focal ischemia: evidence for increased synthesis and anterograde axonal transport. Exp Neurol 154:289–301

  19. Korsching S, Auburger G, Heumann R, Scott J, Thoenen H (1985) Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation. EMBO J 4:1389–1393

  20. Lapchak PA, Araujo DM, Beck KD, Finch CE, Johnson SA, Hefti F (1993) BDNF and trkB mRNA expression in the hippocampal formation of aging rats. Neurobiol Aging 14:121–126

  21. Lauterborn JC, Rivera S, Stinis CT, Hayes VY, Isackson PJ, Gall CM (1996) Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: evidence for immediate-early gene responses from specific promoters. J Neurosci 16:7428–7436

  22. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

  23. Liu QR, Lu L, Zhu XG, Gong JP, Shaham Y, Uhl GR (2006) Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res 1067:1–12

  24. Masoudi R, Ioannou MS, Coughlin MD, Pagadala P, Neet KE, Clewes O et al (2009) Biological activity of nerve growth factor precursor is dependent upon relative levels of its receptors. J Biol Chem 284:18424–18433

  25. Mladenovic Djordjevic A, Perovic M, Tesic V, Tanic N, Rakic L, Ruzdijic S, Kanazir S (2010) Long-term dietary restriction modulates the level of presynaptic proteins in the cortex and hippocampus of the aging rat. Neurochem Int 56:250–255

  26. Nair A, Vadodaria KC, Banerjee SB, Benekareddy M, Dias BG, Duman RS, Vaidya VA (2007) Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus. Neuropsychopharmacology 32:1504–1519

  27. Pang PT, Lu B (2004) Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF. Aging Res Rev 3:407–430

  28. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487–491

  29. Pattabiraman PP, Tropea D, Chiaruttini C, Tongiorgi E, Cattaneo A, Domenici L (2005) Neuronal activity regulates the developmental expression and subcellular localization of cortical BDNF mRNA isoforms in vivo. Mol Cell Neurosci 28:556–570

  30. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 7:695–702

  31. Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32

  32. Rattiner LM, Davis M, French CT, Ressler KJ (2004) Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J Neurosci 24:4796–4806

  33. Santi S, Cappello S, Riccio M, Bergami M, Aicardi G, Schenk U, Matteoli M, Canossa M (2006) Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance. EMBO J 25:4372–4380

  34. Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221:555–563

  35. Seidah NG, Benjannet S, Pareek S, Chrétien M, Murphy RA (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 379:247–250

  36. Silhol M, Arancibia S, Maurice T, Tapia-Arancibia L (2007) Spatial memory training modifies the expression of brain-derived neurotrophic factor tyrosine kinase receptors in young and aged rats. Neuroscience 146:962–973

  37. Silhol M, Arancibia S, Perrin D, Maurice T, Alliot J, Tapia-Arancibia L (2008) Effect of aging on brain-derived neurotrophic factor, proBDNF, and their receptors in the hippocampus of Lou/C rats. Rejuvenation Res 11:1031–1040

  38. Singh KK, Park KJ, Hong EJ, Kramer BM, Greenberg ME, Kaplan DR, Miller FD (2008) Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration. Nat Neurosci 11:649–658

  39. Song W, Volosin M, Cragnolini AB, Hempstead BL, Friedman WJ (2010) ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J Neurosci 30(46):15608–15615

  40. Sugaya K, Greene R, Personett D, Robbins M, Kent C, Bryan D, Skiba E, Gallagher M, McKinney M (1998) Septo-hippocampal cholinergic and neurotrophin markers in age-induced cognitive decline. Neurobiol Aging 19:351–361

  41. Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S (2008) New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 59(1):201–220

  42. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463

  43. Thoenen H (2000) Neurotrophins and activity-dependent plasticity. Prog Brain Res 128:183–191

  44. Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M, Persson H (1993) Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10:475–489

  45. Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD (2002) From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem 9:224–237

  46. Urra S, Escudero CA, Ramos P, Lisbona F, Allende E, Covarrubias P, Parraguez JI, Zampieri N, Chao MV, Annaert W, Bronfman FC (2007) TrkA receptor activation by nerve growth factor induces shedding of the p75 neurotrophin receptor followed by endosomal gamma-secretase-mediated release of the p75 intracellular domain. J Biol Chem 282:7606–7615

  47. Volosin M, Trotter C, Cragnolini A, Kenchappa RS, Light M, Hempstead BL, Carter BD, Friedman WJ (2008) Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures. J Neurosci 28:9870–9879

  48. Weskamp G, Schlöndorff J, Lum L, Becherer JD, Kim TW, Saftig P, Hartmann D, Murphy G, Blobel CP (2004) Evidence for a critical role of the tumor necrosis factor alpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR). J Biol Chem 279:4241–4249

  49. Yang J, Siao CJ, Nagappan G, Marinic T, Jing D, McGrath K et al (2009) Neuronal release of proBDNF. Nat Neurosci 12:113–115

Download references

Acknowledgments

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, grant. no. ON 173056. We wish to express our gratitude to Dr. Olivera Nesic–Taylor from the University of Texas Medical Branch, Galveston, TX, for her generous gift of antibodies.

Author information

Correspondence to Selma Kanazir.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1
figure6

Online Resource 1 Expression of exon I-, II-, III-, IV- and VI-containing BDNF transcripts, total BDNF and total NGF during aging. Semiquantitive RT-PCR analysis was used to determine the levels of specific mRNAs in cortex and hippocampus of 6-, 12-, 18- and 24-month-old rats. All RT-PCR reactions were performed in triplicate and at least two independent RT reactions. PCR products were resolved in a 2 % agarose gel and visualized by staining with ethidium bromide. Multi-Analyst/PC Software Image Analysis System (Bio-Rad Gel Doc 1000) was used for densitometry analysis (JPEG 21 kb)

ESM 2
figure7

Online Resource 2 Aging did not induce neurodegeneration even when pAkt was decreased in the hippocampus. Representative photomicrographs of the cingulate/retrosplenial cortex (A) and dorsal hippocampus (B) in 24-month-old rats following Fluoro-Jade B staining of brain sections. Scattered FJB-positive neurons with smaller cell bodies and short processes are present in the same brain areas of (+)MK-801-treated animals which served as a positive control (C,D). Scale bar =50 μm (JPEG 68 kb)

High Resolution Image (TIFF 2014 kb)

High Resolution Image (TIFF 2355 kb)

About this article

Cite this article

Perovic, M., Tesic, V., Mladenovic Djordjevic, A. et al. BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat. AGE 35, 2057–2070 (2013). https://doi.org/10.1007/s11357-012-9495-6

Download citation

Keywords

  • Aging
  • BDNF and proBDNF
  • NGF and proNGF
  • BDNF mRNA isoforms
  • Cortex and hippocampus