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Sexually Dimorphic Expression of Reelin in the Brain of a Mouse Model of Alzheimer Disease

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Abstract

Recent evidence highlights the protective role of reelin against amyloid β (Aβ)-induced synaptic dysfunction and cognitive impairment in Alzheimer disease (AD). In this study, exploiting TgCRND8 mice that overexpress a mutant form of amyloid β precursor protein (AβPP) and display an early onset of AD neuropathological signs, we addressed the question whether changes of reelin expression eventually precede the appearance of Aβ-plaques in a sex-dependent manner. We show that sex-associated and brain region-specific differences in reelin expression appear long before Aβ-plaque formation. However, in spite of a downregulation of reelin expression compared to males, TgCRND8 females display fewer Aβ-plaques, suggesting that additional factors, other than sex and reelin level, influence amyloidosis in this mouse model.

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References

  • Arnaud L, Ballif BA, Cooper JA (2003) Regulation of protein tyrosine kinase signaling by substrate degradation during brain development. Mol Cell Biol 23:9293–9302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA (2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62:685–691

    Article  PubMed  Google Scholar 

  • Beffert U, Weeber EJ, Durudas A, Qiu S, Masiulis I, Sweatt JD, Li WP, Adelmann G, Frotscher M, Hammer RE, Herz J (2005) Modulation of synaptic plasticity and memory by reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 47:567–579

    Article  CAS  PubMed  Google Scholar 

  • Bellucci A, Rosi MC, Grossi C, Fiorentini A, Luccarini I, Casamenti F (2007) Abnormal processing of tau in the brain of aged TgCRND8 mice. Neurobiol Dis 27:328–338

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J (2005) Reelin modulates NMDA receptor activity in cortical neurons. J Neurosci 25:8209–8216

    Article  CAS  PubMed  Google Scholar 

  • Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J et al (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276:21562–21570

    Article  CAS  PubMed  Google Scholar 

  • Cooper JA (2008) A mechanism for inside-out lamination in the neocortex. Trends Neurosci 31:113–119

    Article  CAS  PubMed  Google Scholar 

  • D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T (1999) Reelin is a ligand for lipoprotein receptors. Neuron 24:471–479

    Article  PubMed  Google Scholar 

  • Doehner J, Knuesel I (2010) Reelin-mediated signaling during normal and pathological forms of aging. Aging Dis 1:12–29

    PubMed  PubMed Central  Google Scholar 

  • Dong E, Caruncho H, Liu WS, Smalheiser NR, Grayson DR, Costa E, Guidotti A (2003) A reelin-integrin receptor interaction regulates arc mRNA translation in synaptoneurosomes. Proc Natl Acad Sci U S A 100:5479–5484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durakoglugil MS, Chen Y, White CL, Kavalali ET, Herz J (2009) Reelin signaling antagonizes beta-amyloid at the synapse. Proc Natl Acad Sci U S A 106:15938–15943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feher A, Juhasz A, Pakaski M, Kalman J, Janka Z (2015) Genetic analysis of the RELN gene: gender specific association with Alzheimer’s disease. Psychiatry Res 230:716–718

    Article  CAS  PubMed  Google Scholar 

  • Feng L, Allen NS, Simo S, Cooper JA (2007) Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development. Genes Dev 21:2717–2730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Förster E (2014) Reelin, neuronal polarity and process orientation of cortical neurons. Neuroscience 269:102–111

    Article  PubMed  Google Scholar 

  • Förster E, Bock HH, Herz J, Chai X, Frotscher M, Zhao S (2010) Emerging topics in reelin function. Eur J Neurosci 31:1511–1518

    PubMed  PubMed Central  Google Scholar 

  • Fuso A, Nicolia V, Pasqualato A, Fiorenza MT, Cavallaro RA, Scarpa S (2011) Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency. Neurobiol Aging 32:187–199

    Article  CAS  PubMed  Google Scholar 

  • Fuso A, Cavallaro RA, Nicolia V, Scarpa S (2012) PSEN1 promoter demethylation in hyperhomocysteinemic TgCRND8 mice is the culprit, not the consequence. Curr Alzheimer Res 9:527–535

    Article  CAS  PubMed  Google Scholar 

  • Granger MW, Franko B, Taylor MW, Messier C, George-Hyslop PS, Bennett SA (2016) A TgCRND8 mouse model of Alzheimerʼs disease exhibits sexual dimorphisms in behavioral indices of cognitive reserve. J Alzheimers Dis 51:757–773

    Article  CAS  PubMed  Google Scholar 

  • Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783

    Article  PubMed  PubMed Central  Google Scholar 

  • Henderson VW, Buckwalter JG (1994) Cognitive deficits of men and women with Alzheimerʼs disease. Neurology 44:90–96

    Article  CAS  PubMed  Google Scholar 

  • Herring A, Donath A, Steiner KM, Widera MP, Hamzehian S, Kanakis D, Kölble K, ElAli A, Hermann DM, Paulus W, Keyvani K (2012) Reelin depletion is an early phenomenon of Alzheimerʼs pathology. J Alzheimers Dis 30:963–979

    PubMed  Google Scholar 

  • Hoe HS, Tran TS, Matsuoka Y, Howell BW, Rebeck GW (2006) DAB1 and reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. J Biol Chem 281:35176–35185

    Article  CAS  PubMed  Google Scholar 

  • Howell BW, Herrick TM, Cooper JA (1999) Reelin-induced tyrosine phosphorylation of disabled 1 during neuronal positioning. Genes Dev 13:643–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kerjan G, Gleeson JG (2007) A missed exit: reelin sets in motion Dab1 polyubiquitination to put the break on neuronal migration. Genes Dev 21:2850–2854

    Article  CAS  PubMed  Google Scholar 

  • Knuesel I, Nyffeler M, Mormède C, Muhia M, Meyer U, Pietropaolo S, Yee BK, Pryce CR, LaFerla FM, Marighetto A, Feldon J (2009) Age-related accumulation of reelin in amyloid-like deposits. Neurobiol Aging 30:697–716

    Article  CAS  PubMed  Google Scholar 

  • Kobro-Flatmoen A, Nagelhus A, Witter MP (2016) Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer’s disease. Neurobiol Dis 93:172–183

    Article  CAS  PubMed  Google Scholar 

  • Koie M, Okumura K, Hisanaga A, Kamei T, Sasaki K, Deng M et al (2014) Cleavage within reelin repeat 3 regulates the duration and range of the signaling activity of reelin protein. J Biol Chem 289:12922–12930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee GH, D’Arcangelo G (2016) New insights into reelin-mediated signaling pathways. Front Cell Neurosci 10:122

    PubMed  PubMed Central  Google Scholar 

  • Lussier A, Weeber E, Rebeck W (2016) Reelin proteolysis affects signaling related to normal synapse function and neurodegeneration. Front Cell Neurosci 10:75

    Article  PubMed  PubMed Central  Google Scholar 

  • Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37–48

    Article  PubMed  PubMed Central  Google Scholar 

  • Naurin S, Hansson B, Hasselquist D, Kim Y-H, Bensch S (2011) The sex-biased brain: sexual dimorphism in gene expression in two species of songbirds. BMC Genomics 12:37

    Article  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson C (1998) The mouse brain in stereotaxic coordinates. Academic Press Limited, London

    Google Scholar 

  • Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A, Caruncho HJ (1998) Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats. Proc Natl Acad Sci U S A 95:3221–3226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piscopo P, Canterini S, Carletti V, Rosa P, Crestini A, Fiorenza MT, Confaloni A (2013) Sex effect on presenilins expression in post-natal rat brain. Adv Biosci Biotechnol 4:1086–1094

    Article  Google Scholar 

  • Proust-Lima C, Amieva H, Letenneur L, Orgogozo JM, Jacqmin-Gadda H, Dartigues JF (2008) Gender and education impact on brain aging: a general cognitive factor approach. Psychol Aging 23:608–620

    Article  PubMed  Google Scholar 

  • Pujadas L, Rossi D, Andrés R, Teixeira CM, Serra-Vidal B, Parcerisas A, Maldonado R, Giralt E, Carulla N, Soriano E (2014) Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimerʼs disease. Nat Commun 5:3443

    Article  PubMed  Google Scholar 

  • Ramos-Moreno T, Galazo MJ, Porrero C, Martínez-Cerdeño V, Clascá F (2006) Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted reelin in the adult rat brain. Eur J Neurosci 23:401–422

    Article  PubMed  Google Scholar 

  • Read S, Pedersen NL, Gatz M, Berg S, Vuoksimaa E, Malmberg B, Johansson B, McClearn GE (2006) Sex differences after all those years? Heritability of cognitive abilities in old age. J Gerontol B Psychol Sci Soc Sci 61:137–143

    Article  Google Scholar 

  • Romano E, Fuso A, Laviola G (2013) Nicotine restores wt-like levels of reelin and GAD67 gene expression in brain of heterozygous reeler mice. Neurotox Res 24:205–215

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB, Haass C (1996) The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann N Y Acad Sci 17:57–64

    Article  Google Scholar 

  • Steele JW, Brautigam H, Short JA, Sowa A, Shi M, Yadav A, Weaver CM, Westaway D, Fraser PE, St George-Hyslop PH, Gandy S, Hof PR, Dickstein DL (2014) Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer’s disease mouse model. J Comp Neurol 522:2319–2335

    Article  PubMed  PubMed Central  Google Scholar 

  • Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J (2002) Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J Biol Chem 277:39944–39952

    Article  CAS  PubMed  Google Scholar 

  • Zhao S, Frotscher M (2010) Go or stop? Divergent roles of reelin in radial neuronal migration. Neuroscientist 16:421–434

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the EC 7th Framework Program, Grant No. 278486 “Develage” and Ateneo 2014 Sapienza to SS and MTF.

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Authors and Affiliations

  1. Department of Psychology, Section of Neuroscience and “Daniel Bovet” Neurobiology Research Center, Sapienza University of Rome, 00185, Rome, Italy

    Giampiero Palladino, Sonia Canterini, Andrea Fuso, Franco Mangia & Maria Teresa Fiorenza

  2. Department of Surgery “P. Valdoni”, Sapienza University of Rome, 00185, Rome, Italy

    Vincenzina Nicolia, Viviana Ciraci & Sigfrido Scarpa

  3. Institute of Neurology Medical University of Vienna, Vienna, Austria

    Gabor G. Kovacs

  4. European Center for Brain Research (CERC)/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy

    Andrea Fuso

Authors
  1. Giampiero Palladino
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  2. Vincenzina Nicolia
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  3. Gabor G. Kovacs
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  4. Sonia Canterini
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  5. Viviana Ciraci
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  6. Andrea Fuso
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  7. Franco Mangia
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  8. Sigfrido Scarpa
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  9. Maria Teresa Fiorenza
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Corresponding author

Correspondence to Maria Teresa Fiorenza.

Electronic Supplementary Material

List of antibodies directed to tau and specific phospho-tau epitopes and relative immunohistochemistry staining and protocols are summarized in supplementary Table 1 and supplementary Fig. 1.

Supplementary Table 1

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Supplementary Fig. 1

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Palladino, G., Nicolia, V., Kovacs, G.G. et al. Sexually Dimorphic Expression of Reelin in the Brain of a Mouse Model of Alzheimer Disease. J Mol Neurosci 61, 359–367 (2017). https://doi.org/10.1007/s12031-016-0865-x

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  • DOI: https://doi.org/10.1007/s12031-016-0865-x

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