Skip to main content
SpringerLink
Log in

Reduced apurinic/apyrimidinic endonuclease 1 activity and increased DNA damage in mitochondria are related to enhanced apoptosis and inflammation in the brain of senescence- accelerated P8 mice (SAMP8)

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

The senescence- accelerated mouse prone 8 (SAMP8) is a well- characterized animal model of senescence that shows early age- related neurodegeneration with impairment in learning and memory skills when compared with control senescence- resistant mice (SAMR1). In the current study, we investigated whether such impairment could be partly due to changes in mitochondrial DNA (mtDNA) repair capacity and mitochondrial DNA damage in the brain of SAMP8 mice. Besides we studied whether these potential changes were related to modifications in two major processes likely involved in aging and neurodegeneration: apoptosis and inflammation. We observed that the specific activity of one of the main mtDNA repair enzymes, the mitochondrial APE1, showed an age- related reduction in SAMP8 animals, while in SAMR1 mice mitochondrial APE1 increased with age. The reduction in mtAPE1 activity in SAMP8 animals was associated with increased levels of the DNA oxidative damage marker 8oxodG in mtDNA. Our results also indicate that these changes were related to a premature increase in apoptotic events and inflammation in the brain of SAMP8 mice when compared to SAMR1 counterparts. We suggest that the premature neurodegenerative phenotype observed in SAMP8 animals might be due, at least in part, to changes in the processing of mtDNA oxidative damage, which would lead to enhancement of apoptotic and inflammatory processes.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Barja G (2004) Free radicals and aging. Trends Neurosci 27:595–600

    Article  CAS  PubMed  Google Scholar 

  • Barja G, Herrero A (2000) Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J 14:312–318

    CAS  PubMed  Google Scholar 

  • Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA, Poon HF (2005) The senescence-accelerated prone mouse (SAMP8): a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer’s disease. Exp Gerontol 40:774–783

    Article  CAS  PubMed  Google Scholar 

  • Caballero B, Vega-Naredo I, Sierra V, Huidobro-Fernandez C, Soria-Valles C, De Gonzalo-Calvo D, Tolivia D, Pallas M, Camins A, Rodriguez-Colunga MJ, Coto-Montes A (2009) Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. J Pineal Res 46:106–114

    Article  CAS  PubMed  Google Scholar 

  • Cantuti-Castelvetri I, Lin MT, Zheng K, Keller-McGandy CE, Betensky RA, Johns DR, Beal MF, Standaert DG, Simon DK (2005) Somatic mitochondrial DNA mutations in single neurons and glia. Neurobiol Aging 26:1343–1355

    Article  CAS  PubMed  Google Scholar 

  • Canugovi C, Shamanna RA, Croteau DL, Bohr VA (2014) Base excision DNA repair levels in mitochondrial lysates of Alzheimer’s disease. Neurobiol Aging 35:1293–1300

    Article  CAS  PubMed  Google Scholar 

  • Cheng XR, Zhou WX, Zhang YX (2014) The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model. Ageing Res Rev 13C:13–37

    Article  Google Scholar 

  • Choi JY, Kim HS, Kang HK, Lee DW, Choi EM, Chung MH (1999) Thermolabile 8-hydroxyguanine DNA glycosylase with low activity in senescence-accelerated mice due to a single-base mutation. Free Radic Biol Med 27:848–854

    Article  CAS  PubMed  Google Scholar 

  • Cuesta S, Kireev R, Forman K, Garcia C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (2010) Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8). Exp Gerontol 45:950–956

    Article  CAS  PubMed  Google Scholar 

  • Cuesta S, Kireev R, Garcia C, Forman K, Escames G, Vara E, Tresguerres JA (2011) Beneficial effect of melatonin treatment on inflammation, apoptosis and oxidative stress on pancreas of a senescence accelerated mice model. Mech Ageing Dev 132:573–582

    Article  CAS  PubMed  Google Scholar 

  • Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10:131–138

    Article  CAS  PubMed  Google Scholar 

  • Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P (2014) Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Front Mol Neurosci 7:104

    PubMed  PubMed Central  Google Scholar 

  • Flood JF, Morley JE (1993) Age-related changes in footshock avoidance acquisition and retention in senescence accelerated mouse (SAM). Neurobiol Aging 14:153–157

    Article  CAS  PubMed  Google Scholar 

  • Forman K, Vara E, Garcia C, Kireev R, Cuesta S, Acuna-Castroviejo D, Tresguerres JA (2010) Beneficial effects of melatonin on cardiological alterations in a murine model of accelerated aging. J Pineal Res 49:312–320

    Article  CAS  PubMed  Google Scholar 

  • Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Matas S, Paul RK, Molina-Martinez P, Palacios H, Gutierrez VM, Corpas R, Pallas M, Cristofol R, de Cabo R, Sanfeliu C (2015) In vitro caloric restriction induces protective genes and functional rejuvenation in senescent SAMP8 astrocytes. Aging Cell 14:334–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gredilla R (2010) DNA damage and base excision repair in mitochondria and their role in aging. J Aging Res 2011:257093

    PubMed  PubMed Central  Google Scholar 

  • Gredilla R, Stevnsner T (2012) Mitochondrial base excision repair assays. Methods Mol Biol 920:289–304

    Article  CAS  PubMed  Google Scholar 

  • Gredilla R, Garm C, Holm R, Bohr VA, Stevnsner T (2010) Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging 31:993–1002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gredilla R, Weissman L, Yang JL, Bohr VA, Stevnsner T (2012) Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer’s disease. Neurobiol Aging 33:694–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffin WS, Sheng JG, Roberts GW, Mrak RE (1995) Interleukin-1 expression in different plaque types in Alzheimer’s disease: significance in plaque evolution. J Neuropathol Exp Neurol 54:276–281

    Article  CAS  PubMed  Google Scholar 

  • Hegde ML, Hazra TK, Mitra S (2008) Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells. Cell Res 18:27–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer’s disease. Nat Immunol 16:229–236

    Article  CAS  PubMed  Google Scholar 

  • Hiona A, Sanz A, Kujoth GC, Pamplona R, Seo AY, Hofer T, Someya S, Miyakawa T, Nakayama C, Samhan-Arias AK, Servais S, Barger JL, Portero-Otin M, Tanokura M, Prolla TA, Leeuwenburgh C (2010) Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One 5:e11468

    Article  PubMed  PubMed Central  Google Scholar 

  • Jeppesen DK, Bohr VA, Stevnsner T (2011) DNA repair deficiency in neurodegeneration. Prog Neurobiol 94:166–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484

    Article  CAS  PubMed  Google Scholar 

  • Kujoth GC, Bradshaw PC, Haroon S, Prolla TA (2007) The role of mitochondrial DNA mutations in mammalian aging. PLoS Genet 3:e24

    Article  PubMed  PubMed Central  Google Scholar 

  • Kukreja L, Kujoth GC, Prolla TA, Van Leuven F, Vassar R (2014) Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer’s disease. Mol Neurodegener 9:16

    Article  PubMed  PubMed Central  Google Scholar 

  • Leret ML, San Millan JA, Fabre E, Gredilla R, Barja G (2002) Deprenyl protects from MPTP-induced Parkinson-like syndrome and glutathione oxidation in rat striatum. Toxicology 170:165–171

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Cui G, Zhu M, Kang X, Guo H (2014) Neuroinflammation in Alzheimer’s disease: chemokines produced by astrocytes and chemokine receptors. Int J Clin Exp Pathol 7:8342–8355

    PubMed  PubMed Central  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Macchi B, Paola DR, Marino-Merlo F, Felice MR, Cuzzocrea S, Mastino A (2015) Inflammatory and Cell Death Pathways in Brain and Peripheral Blood in Parkinson’s disease. CNS Neurolog Disord Drug Targets 14:313–324

    Article  CAS  Google Scholar 

  • Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melov S (2004) Modeling mitochondrial function in aging neurons. Trends Neurosci 27:601–606

    Article  CAS  PubMed  Google Scholar 

  • Menardo J, Tang Y, Ladrech S, Lenoir M, Casas F, Michel C, Bourien J, Ruel J, Rebillard G, Maurice T, Puel JL, Wang J (2012) Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse Cochlea. Antioxid Redox Signal 16:263–274

    Article  CAS  PubMed  Google Scholar 

  • Mitra S, Izumi T, Boldogh I, Bhakat KK, Chattopadhyay R, Szczesny B (2007) Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein. DNA Repair (Amst) 6:461–469

    Article  CAS  Google Scholar 

  • Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM (2003) Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24:1063–1070

    Article  CAS  PubMed  Google Scholar 

  • Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466

    Article  PubMed  Google Scholar 

  • Riancho JA, Zarrabeitia MT, Amado JA, Olmos JM, Gonzalez-Macias J (1994) Age-related differences in cytokine secretion. Gerontology 40:8–12

    Article  CAS  PubMed  Google Scholar 

  • Rousseaux MW, Marcogliese PC, Qu D, Hewitt SJ, Seang S, Kim RH, Slack RS, Schlossmacher MG, Lagace DC, Mak TW, Park DS (2012) Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. Proc Natl Acad Sci U S A 109:15918–15923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanders LH, McCoy J, Hu X, Mastroberardino PG, Dickinson BC, Chang CJ, Chu CT, Van Houten B, Greenamyre JT (2014) Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson’s disease. Neurobiol Dis 70:214–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato E, Oda N, Ozaki N, Hashimoto S, Kurokawa T, Ishibashi S (1996) Early and transient increase in oxidative stress in the cerebral cortex of senescence-accelerated mouse. Mech Ageing Dev 86:105–114

    Article  CAS  PubMed  Google Scholar 

  • Siddiqui A, Rivera-Sanchez S, Castro Mdel R, Acevedo-Torres K, Rane A, Torres-Ramos CA, Nicholls DG, Andersen JK, Ayala-Torres S (2012) Mitochondrial DNA damage is associated with reduced mitochondrial bioenergetics in Huntington’s disease. Free Radic Biol Med 53:1478–1488

    Article  CAS  PubMed  Google Scholar 

  • Takeda T (2009) Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem Res 34:639–659

    Article  CAS  PubMed  Google Scholar 

  • Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, Tomita Y, Yasuhira K, Hamamoto H, Shimizu K, Ishii M, Yamamuro T (1981) A new murine model of accelerated senescence. Mech Ageing Dev 17:183–194

    Article  CAS  PubMed  Google Scholar 

  • Takemura M, Nakamura S, Akiguchi I, Ueno M, Oka N, Ishikawa S, Shimada A, Kimura J, Takeda T (1993) Beta/A4 proteinlike immunoreactive granular structures in the brain of senescence-accelerated mouse. Am J Pathol 142:1887–1897

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y (2000) Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885:25–31

    Article  CAS  PubMed  Google Scholar 

  • Tian F, Tong TJ, Zhang ZY, McNutt MA, Liu XW (2009) Age-dependent down-regulation of mitochondrial 8-oxoguanine DNA glycosylase in SAM-P/8 mouse brain and its effect on brain aging. Rejuvenation Res 12:209–215

    Article  CAS  PubMed  Google Scholar 

  • Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39:540–543

    Article  CAS  PubMed  Google Scholar 

  • Wanagat J, Cao Z, Pathare P, Aiken JM (2001) Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 15:322–332

    Article  CAS  PubMed  Google Scholar 

  • Weissman L, de Souza-Pinto NC, Stevnsner T, Bohr VA (2007a) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145:1318–1329

    Article  CAS  PubMed  Google Scholar 

  • Weissman L, Jo DG, Sorensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP, Bohr VA (2007b) Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res 35:5545–5555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang JL, Tadokoro T, Keijzers G, Mattson MP, Bohr VA (2010) Neurons efficiently repair glutamate-induced oxidative DNA damage by a process involving CREB-mediated up-regulation of apurinic endonuclease 1. J Biol Chem 285:28191–28199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang JL, Lin YT, Chuang PC, Bohr VA, Mattson MP (2014) BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1. Neuromol Med 16:161–174

    Article  CAS  Google Scholar 

  • Zhu Y, Lee CC, Lam WP, Wai MS, Rudd JA, Yew DT (2007) Cell death in the Purkinje cells of the cerebellum of senescence accelerated mouse (SAMP(8)). Biogerontology 8:537–544

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant from the Complutense University/Community of Madrid to RG (CCG10-UCM/SAL 4798).

Author information

Author notes

  1. R. Torregrosa-Muñumer

    Present address: University of Eastern Finland, Joensuu, Finland

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain

    R. Torregrosa-Muñumer, R. Kireev, J. A. F. Tresguerres & R. Gredilla

  2. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain

    E. Vara

  3. Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, Madrid, Spain

    A. Gómez & G. Barja

Authors
  1. R. Torregrosa-Muñumer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Vara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Kireev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Barja
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. A. F. Tresguerres
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Gredilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Gredilla.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torregrosa-Muñumer, R., Gómez, A., Vara, E. et al. Reduced apurinic/apyrimidinic endonuclease 1 activity and increased DNA damage in mitochondria are related to enhanced apoptosis and inflammation in the brain of senescence- accelerated P8 mice (SAMP8). Biogerontology 17, 325–335 (2016). https://doi.org/10.1007/s10522-015-9612-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-015-9612-x

Keywords

Search

Navigation