Abstract
Mammalian aging is associated with decline in cognitive functions. Studies searching for a cause of cognitive aging initially focused on neuronal loss but quantitative investigations of rat, monkey, and human brain using stereology demonstrated that in normal aging, unlike in neurodegenerative disease, neurons are not lost. Instead, electron microscopic and MRI studies in normal aging monkeys revealed age-related damage to myelin sheaths, loss of axons, and reduction in white matter volume which correlates with cognitive impairments. However, little is known about the cause of myelin defects or associated axon loss. The present study investigates the effect of age on signaling pathways between oligodendroglia and neurons using a custom PCR array to assess the expression of 87 genes of interest in cortical gray matter and white matter from the inferior parietal lobe (IPL) of normal rhesus monkeys ranging in age from 4.2 to 30.4 years old. From this array data, five target genes of interest were selected for further analysis to confirm gene expression and measure protein expression. The most interesting target gene identified is brain-derived neurotrophic factor (BDNF), which was the only gene that was altered at both mRNA and protein levels. In gray matter, BDNF mRNA was decreased. While the level of the mature form of the protein was unchanged, there was a specific decrease in the precursor form of BDNF. These alterations in the BDNF in gray matter could contribute to the vulnerability and loss of the axons with age.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385(6618):729–733. https://doi.org/10.1038/385729a0
Bowley MP, Cabral H, Rosene DL, Peters A (2010) Age changes in myelinated nerve fibers of the cingulate bundle and corpus callosum in the rhesus monkey. J Comp Neurol 518(15):3046–3064. https://doi.org/10.1002/cne.22379
Butzkueven H, Emery B, Cipriani T, Marriott MP, Kilpatrick TJ (2006) Endogenous leukemia inhibitory factor production limits autoimmune demyelination and oligodendrocyte loss. Glia 53(7):696–703. https://doi.org/10.1002/glia.20321
Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309. https://doi.org/10.1038/nrn1078
Chen C-D, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, Abraham CR (2013) The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 33(5):1927–1939. https://doi.org/10.1523/JNEUROSCI.2080-12.2013
Dickstein DL, Weaver CM, Luebke JI, Hof PR (2013) Dendritic spine changes associated with normal aging. Neuroscience 251:21–32. https://doi.org/10.1016/j.neuroscience.2012.09.077
Driscoll I, Martin B, An Y, Maudsley S, Ferrucci L, Mattson MP, Resnick SM (2012) Plasma BDNF is associated with age-related white matter atrophy but not with cognitive function in older, non-demented adults. PLoS One 7(4):e35217. https://doi.org/10.1371/journal.pone.0035217
Du Y, Fischer TZ, Clinton-Luke P, Lercher LD, Dreyfus CF (2006) Distinct effects of p75 in mediating actions of neurotrophins on basal forebrain oligodendrocytes. Mol Cell Neurosci 31(2):366–375. https://doi.org/10.1016/j.mcn.2005.11.001
Duce JA, Podvin S, Hollander W, Kipling D, Rosene DL, Abraham CR (2008) Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia 56(1):106–117. https://doi.org/10.1002/glia.20593
Elkabes S, DiCicco-Bloom EM, Black IB (1996) Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 16(8):2508–2521
Freeman SH, Kandel R, Cruz L, Rozkalne A, Newell K, Frosch MP, Hedley-Whyte ET, Locascio JJ, Lipsitz LA, Hyman BT (2008) Preservation of neuronal number despite age-related cortical brain atrophy in elderly subjects without Alzheimer disease. J Neuropathol Exp Neurol 67(12):1205–1212. https://doi.org/10.1097/NEN.0b013e31818fc72f
Gärtner A, Polnau DG, Staiger V, Sciarretta C, Minichiello L, Thoenen H, Bonhoeffer T, Korte M (2006) Hippocampal long-term potentiation is supported by presynaptic and postsynaptic tyrosine receptor kinase B-mediated phospholipase Cgamma signaling. J Neurosci 26(13):3496–3504. https://doi.org/10.1523/JNEUROSCI.3792-05.2006
Giannaris EL, Rosene DL (2012) A stereological study of the numbers of neurons and glia in the primary visual cortex across the lifespan of male and female rhesus monkeys. J Comp Neurol 520(15):3492–3508. https://doi.org/10.1002/cne.23101
Gómez-Isla T, Price JL, McKeel DW et al (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16(14):4491–4500
Gorski JA, Zeiler SR, Tamowski S, Jones KR (2003) Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci 23(17):6856–6865
Gray K, Ellis V (2008) Activation of pro-BDNF by the pericellular serine protease plasmin. FEBS Lett 582(6):907–910. https://doi.org/10.1016/j.febslet.2008.02.026
Haug H (1985) Are neurons of the human cerebral cortex really lost during aging? A morphometric examination. In: Traber J, Gispen WH (eds) Senile dementia of the azheimer type. Springer Verlag, Berlin, pp 150–163. https://doi.org/10.1007/978-3-642-70644-8_12
Herndon JG, Moss MB, Rosene DL, Killiany RJ (1997) Patterns of cognitive decline in aged rhesus monkeys. Behav Brain Res 87(1):25–34. https://doi.org/10.1016/S0166-4328(96)02256-5
Hinman JD, Chen C-D, Oh S-Y, Hollander W, Abraham CR (2008) Age-dependent accumulation of ubiquitinated 2′,3′-cyclic nucleotide 3′-phosphodiesterase in myelin lipid rafts. Glia 56(1):118–133. https://doi.org/10.1002/glia.20595
Kohama SG, Rosene DL, Sherman LS (2012) Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline. Age (Dordr) 34(5):1093–1110. https://doi.org/10.1007/s11357-011-9357-7
Komulainen P, Pedersen M, Hänninen T, Bruunsgaard H, Lakka TA, Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R (2008) BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA study. Neurobiol Learn Mem 90(4):606–613. https://doi.org/10.1016/j.nlm.2008.07.014
Koshimizu H, Kiyosue K, Hara T, Hazama S, Suzuki S, Uegaki K, Nagappan G, Zaitsev E, Hirokawa T, Tatsu Y, Ogura A, Lu B, Kojima M (2009) Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival. Mol Brain 2(1):27. https://doi.org/10.1186/1756-6606-2-27
Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu CE, Bekris LM, Raskind MA, Galasko DR, Montine TJ (2009) Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One 4(5):e5424. https://doi.org/10.1371/journal.pone.0005424.t002
Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow JC (2005) The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 26(1):115–123. https://doi.org/10.1016/j.neurobiolaging.2004.03.002
Makris N, Papadimitriou GM, van der Kouwe A, Kennedy DN, Hodge SM, Dale AM, Benner T, Wald LL, Wu O, Tuch DS, Caviness VS, Moore TL, Killiany RJ, Moss MB, Rosene DL (2007) Frontal connections and cognitive changes in normal aging rhesus monkeys: a DTI study. Neurobiol Aging 28(10):1556–1567. https://doi.org/10.1016/j.neurobiolaging.2006.07.005
Marner L, Nyengaard JR, Tang Y, Pakkenberg B (2003) Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol 462(2):144–152. https://doi.org/10.1002/cne.10714
Matsuda N, Lu H, Fukata Y, Noritake J, Gao H, Mukherjee S, Nemoto T, Fukata M, Poo M (2009) Differential activity-dependent secretion of brain-derived neurotrophic factor from axon and dendrite. J Neurosci 29(45):14185–14198. https://doi.org/10.1523/JNEUROSCI.1863-09.2009
Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde YA (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11(2):131–133. https://doi.org/10.1038/nn2038
Matsunaga W, Shirokawa T, Isobe K (2004) BDNF is necessary for maintenance of noradrenergic innervations in the aged rat brain. Neurobiol Aging 25(3):341–348. https://doi.org/10.1016/S0197-4580(03)00093-9
Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH, Nave KA (2004) Axonal neuregulin-1 regulates myelin sheath thickness. Science 304(5671):700–689. https://doi.org/10.1126/science.1095862
Michalski B, Fahnestock M (2003) Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Res Mol Brain Res 111(1-2):148–154. https://doi.org/10.1016/S0169-328X(03)00003-2
Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, Koike H, Kamei H, Nabeshima T, Itohara S, Takuma K, Sawada M, Sato J, Yamada K (2011) Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. J Neurosci 31(36):12963–12971. https://doi.org/10.1523/JNEUROSCI.3118-11.2011
Moore TL, Killiany RJ, Herndon JG, Rosene DL (2005) A non-human primate test of abstraction and set shifting: an automated adaptation of the Wisconsin card sorting test. J Neurosci Methods 146(2):165–173. https://doi.org/10.1016/j.jneumeth.2005.02.005
Morrison JH, Hof PR (1997) Life and death of neurons in the aging brain. Science 278(5337):412–419. https://doi.org/10.1126/science.278.5337.412
Noriega NC, Kohama SG, Urbanski HF (2010) κMicroarray analysis of relative gene expression stability for selection of internal reference genes in the rhesus macaque brain. BMC Mol Biol 11(1):47. https://doi.org/10.1186/1471-2199-11-47
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(5695):487–491. https://doi.org/10.1126/science.1100135
Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93(6):1412–1421. https://doi.org/10.1111/j.1471-4159.2005.03135.x
Perovic M, Tesic V, Mladenovic Djordjevic A, Smiljanic K, Loncarevic-Vasiljkovic N, Ruzdijic S, Kanazir S (2013) BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat. Age (Dordr) 35(6):2057–2070. https://doi.org/10.1007/s11357-012-9495-6
Peters A, Kemper T (2012) A review of the structural alterations in the cerebral hemispheres of the aging rhesus monkey. Neurobiol Aging 33(10):2357–2372. https://doi.org/10.1016/j.neurobiolaging.2011.11.015
Peters A, Sethares C (2003) Is there remyelination during aging of the primate central nervous system? J Comp Neurol 460(2):238–254. https://doi.org/10.1002/cne.10639
Peters A, Moss MB, Sethares C (2000) Effects of aging on myelinated nerve fibers in monkey primary visual cortex. J Comp Neurol 419(3):364–376. https://doi.org/10.1002/(SICI)1096-9861(20000410)419:3<364::AID-CNE8>3.0.CO;2-R
Peters A, Sethares C, Moss MB (2010) How the primate fornix is affected by age. J Comp Neurol 518(19):3962–3980. https://doi.org/10.1002/cne.22434
Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2(1):24–32. https://doi.org/10.1038/35049004
Roberts DE, Killiany RJ, Rosene DL (2012) Neuron numbers in the hypothalamus of the normal aging rhesus monkey: stability across the adult lifespan and between the sexes. J Comp Neurol 520(6):1181–1197. https://doi.org/10.1002/cne.22761
Romanczyk TB, Weickert CS, Webster MJ, Herman MM, Akil M, Kleinman JE (2002) Alterations in trkB mRNA in the human prefrontal cortex throughout the lifespan. Eur J Neurosci 15(2):269–280. https://doi.org/10.1046/j.0953-816x.2001.01858.x
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(3):247–250. https://doi.org/10.1016/0014-5793(95)01520-5
Shirakabe K, Wakatsuki S, Kurisaki T, Fujisawa-Sehara A (2000) Roles of meltrin beta /ADAM19 in the processing of neuregulin. J Biol Chem 276(12):9352–9358. https://doi.org/10.1074/jbc.M007913200
Shobin E, Bowley MP, Estrada LI, Heyworth NC, Orczykowski ME, Eldridge SA, Calderazzo SM, Mortazavi F, Moore TL, Rosene DL (2017) Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey. GeroScience 39(2):199–220. https://doi.org/10.1007/s11357-017-9965-y
Sloane JA, Pietropaolo MF, Rosene DL, Moss MB, Peters A, Kemper T, Abraham CR (1997) Lack of correlation between plaque burden and cognition in the aged monkey. Acta Neuropathol 94(5):471–478. https://doi.org/10.1007/s004010050735
Sloane JA, Hollander W, Moss MB, Rosene DL, Abraham CR (1999) Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol Aging 20(4):395–405. https://doi.org/10.1016/S0197-4580(99)00066-4
Sloane JA, Hollander W, Rosene DL, Moss MB, Kemper T, Abraham CR (2000) Astrocytic hypertrophy and altered GFAP degradation with age in subcortical white matter of the rhesus monkey. Brain Res 862(1-2):1–10. https://doi.org/10.1016/S0006-8993(00)02059-X
Sobreviela T, Pagcatipunan M, Kroin JS, Mufson EJ (1996) Retrograde transport of brain-derived neurotrophic factor (BDNF) following infusion in neo- and limbic cortex in rat: relationship to BDNF mRNA expressing neurons. J Comp Neurol 375(3):417–444. https://doi.org/10.1002/(SICI)1096-9861(19961118)375:3<417::AID-CNE6>3.0.CO;2-5
Stygar D, Masironi B, Eriksson H, Sahlin L (2007) Studies on estrogen receptor (ER) and responses on gene regulation in peripheral blood leukocytes in vivo using selective ER agonists. J Endocrinol 194(1):101–119. https://doi.org/10.1677/JOE-06-0060
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(22):5455–5463. https://doi.org/10.1523/JNEUROSCI.5123-04.2005
Terry RD, DeTeresa R, Hansen LA (1987) Neocortical cell counts in normal human adult aging. Ann Neurol 21(6):530–539. https://doi.org/10.1002/ana.410210603
Tigges J, Gordon TP, McClure HM, Hall EC, Peters A (1988) Survival rate and life span of rhesus monkeys at the Yerkes Regional Primate Research Center. Am J Primatol 15(3):263–273. https://doi.org/10.1002/ajp.1350150308
Vernooij MW, de Groot M, van der Lugt A, Ikram MA, Krestin GP, Hofman A, Niessen WJ, Breteler MMB (2008) White matter atrophy and lesion formation explain the loss of structural integrity of white matter in aging. NeuroImage 43(3):470–477. https://doi.org/10.1016/j.neuroimage.2008.07.052
Wang KC, Kim JA, Sivasankaran R, Segal R, He Z (2002) P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420(6911):74–78. https://doi.org/10.1038/nature01176
Whitehouse P, Price D, Struble R, Clark A, Coyle J, Delon M (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215(4537):1237–1239. https://doi.org/10.1126/science.7058341
Wu H, Friedman WJ, Dreyfus CF (2004) Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals. J Neurosci Res 76(1):76–85. https://doi.org/10.1002/jnr.20060
Yamamori H, Hashimoto R, Ishima T, Kishi F, Yasuda Y, Ohi K, Fujimoto M, Umeda-Yano S, Ito A, Hashimoto K, Takeda M (2013) Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. Neurosci Lett 556:37–41. https://doi.org/10.1016/j.neulet.2013.09.059
Yang J, Siao C-J, Nagappan G, Marinic T, Jing D, McGrath K, Chen ZY, Mark W, Tessarollo L, Lee FS, Lu B, Hempstead BL (2009) Neuronal release of proBDNF. Nat Neurosci 12(2):113–115. https://doi.org/10.1038/nn.2244
Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK, Ambinder R, Tao Q (2005) The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res 11(18):6442–6449. https://doi.org/10.1158/1078-0432.CCR-05-0267
Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T, Shiina A, Hashimoto T, Kanahara N, Hasegawa T, Enohara M, Kimura A, Iyo M, Hashimoto K (2012) Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One 7(8):e42676. https://doi.org/10.1371/journal.pone.0042676
Acknowledgements
We thank Dr. Shelley Russek for allowing the use of the RT-PCR machine in her laboratory for this study as well as helpful discussions about the pro-BDNF antibody.
Funding
This work was supported by National Institute of Health Grants: P01-AG000001, P51-RR00165, R01-AG043640, R01-AG042512, T32-GM008541.
Author information
Authors and Affiliations
Contributions
AAR and DLR designed the study and drafted the manuscript. AAR, CRA, and DLR determined genes included on the PCR array. AAR completed all experiments and analyses.
Corresponding author
Ethics declarations
All procedures were in accord with NIH guidelines and approved by the Institutional Animal Care and Use Committee of BUMC.
About this article
Cite this article
Robinson, A.A., Abraham, C.R. & Rosene, D.L. Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys. GeroScience 40, 31–47 (2018). https://doi.org/10.1007/s11357-018-0006-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-018-0006-2