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Cited by 30Alzheimer's disease research and treatmentsFunctional Brain Connectivity StudiesNeuroscience and Neuropharmacology Research

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer’s disease

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Rosales Jubal, Eduardo, Schwalm, Miriam, dos Santos Guilherme, Malena, Schuck, Florian, Reinhardt, Sven, Tose, Amanda, Barger, Zeke, Roesler, Mona K. +6 more·2021·Scientific Reports
DOI 10.1038/s41598-021-85912-0PMC PMC7988040
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Abstract

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer’s disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer’s disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

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  1. [1]Brookmeyer R Gray S Kawas C Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset Am. J. Public Health 1998 88 1337 1342 10.2105/ajph.88.9.1337 9736873 PMC1509089 · DOI
  2. [2]Birks JS Harvey RJ Donepezil for dementia due to Alzheimer's disease Cochrane Database Syst. Rev. 2018 6 CD001190 10.1002/14651858.CD001190.pub3 29923184 PMC6513124 · DOI · Paper page
  3. [4]Reiman EM Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: A case-control study Lancet Neurol. 2012 11 1048 1056 10.1016/S1474-4422(12)70228-4 23137948 PMC4181671 · DOI · Paper page
  4. [5]Benilova I Karran E De Strooper B The toxic Abeta oligomer and Alzheimer's disease: An emperor in need of clothes Nat. Neurosci. 2012 15 349 357 10.1038/nn.3028 22286176 · DOI · Paper page
  5. [6]Murphy MP LeVine H 3rd Alzheimer's disease and the amyloid-beta peptide J. Alzheimers Dis. 2010 19 311 323 10.3233/JAD-2010-1221 20061647 PMC2813509 · DOI · Paper page
  6. [7]Masliah E Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease Neurology 2001 56 127 129 10.1212/WNL.56.1.127 11148253 · DOI · Paper page
  7. [8]Brouillette J The effects of soluble Abeta oligomers on neurodegeneration in Alzheimer's disease Curr. Pharm Des. 2014 20 2506 2519 10.2174/13816128113199990498 23859546 · DOI
  8. [9]Serrano-Pozo A Frosch MP Masliah E Hyman BT Neuropathological alterations in Alzheimer disease Cold Spring Harb. Perspect. Med. 2011 1 a006189 10.1101/cshperspect.a006189 22229116 PMC3234452 · DOI · Paper page
  9. [10]Jagust W Is amyloid-beta harmful to the brain? Insights from human imaging studies Brain J. Neurol. 2016 139 23 30 10.1093/brain/awv326 PMC4990654 26614753 · DOI · Paper page
  10. [11]Voevodskaya O Altered structural network organization in cognitively normal individuals with amyloid pathology Neurobiol. Aging 2018 64 15 24 10.1016/j.neurobiolaging.2017.11.014 29316528 · DOI
  11. [12]Busche MA Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease Science 2008 321 1686 1689 10.1126/science.1162844 18802001 · DOI · Paper page
  12. [13]Kuchibhotla KV Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks Neuron 2008 59 214 225 10.1016/j.neuron.2008.06.008 18667150 PMC2578820 · DOI · Paper page
  13. [14]Garaschuk O Imaging microcircuit function in healthy and diseased brain Exp. Neurol. 2013 242 41 49 10.1016/j.expneurol.2012.02.009 22370088 · DOI
  14. [15]Eichhoff G Busche MA Garaschuk O In vivo calcium imaging of the aging and diseased brain Eur. J. Nucl. Med. Mol. Imaging 2008 35 Suppl 1 S99 106 10.1007/s00259-007-0709-6 18193219 · DOI
  15. [16]Lerdkrai C Intracellular Ca(2+) stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease Proc. Natl. Acad. Sci. U.S.A. 2018 115 E1279 E1288 10.1073/pnas.1714409115 29358403 PMC5819404 · DOI
  16. [17]Palop JJ Mucke L Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: From synapses toward neural networks Nat. Neurosci. 2010 13 812 818 10.1038/nn.2583 20581818 PMC3072750 · DOI · Paper page
  17. [18]Grienberger C Staged decline of neuronal function in vivo in an animal model of Alzheimer's disease Nat. Commun. 2012 3 774 10.1038/ncomms1783 22491322 PMC3337977 · DOI
  18. [19]Haberman RP Branch A Gallagher M Targeting neural hyperactivity as a treatment to stem progression of late-onset Alzheimer's disease Neurotherapeutics 2017 14 662 676 10.1007/s13311-017-0541-z 28560709 PMC5509635 · DOI
  19. [20]Arnoux I Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease Elife 2018 10.7554/eLife.38744 30179155 PMC6156080 · DOI
  20. [21]Ellwardt E Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis Nat. Neurosci. 2018 21 1392 1403 10.1038/s41593-018-0193-2 30258239 · DOI
  21. [22]Willmore B Tolhurst DJ Characterizing the sparseness of neural codes Network 2001 12 255 270 10.1080/net.12.3.255.270 11563529 · DOI
  22. [23]Bullmore E Sporns O Complex brain networks: Graph theoretical analysis of structural and functional systems Nat. Rev. Neurosci. 2009 10 186 198 10.1038/nrn2575 19190637 · DOI · Paper page
  23. [24]Bullmore E Sporns O The economy of brain network organization Nat. Rev. Neurosci. 2012 13 336 349 10.1038/nrn3214 22498897 · DOI · Paper page
  24. [25]Sporns O Contributions and challenges for network models in cognitive neuroscience Nat. Neurosci. 2014 17 652 660 10.1038/nn.3690 24686784 · DOI
  25. [26]Sporns O Graph theory methods: Applications in brain networks Dialogues Clin. Neurosci. 2018 20 111 121 10.31887/DCNS.2018.20.2/osporns 30250388 PMC6136126 · DOI
  26. [27]Sporns O Networks of the Brain 2010 Cambridge, MA MIT Press
  27. [28]Mijalkov M BRAPH: A graph theory software for the analysis of brain connectivity PLoS ONE 2017 12 e0178798 10.1371/journal.pone.0178798 28763447 PMC5538719 · DOI
  28. [29]Rubinov M Sporns O Complex network measures of brain connectivity: Uses and interpretations Neuroimage 2010 52 1059 1069 10.1016/j.neuroimage.2009.10.003 19819337 · DOI · Paper page
  29. [30]Dai Z He Y Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer's disease Neurosci. Bull. 2014 30 217 232 10.1007/s12264-013-1421-0 24733652 PMC5562665 · DOI · Paper page
  30. [31]He Y Chen Z Gong G Evans A Neuronal networks in Alzheimer's disease Neuroscientist 2009 15 333 350 10.1177/1073858409334423 19458383 · DOI
  31. [32]Pereira JB Abnormal structural brain connectome in individuals with preclinical Alzheimer's disease Cereb. Cortex 2018 28 3638 3649 10.1093/cercor/bhx236 29028937 · DOI
  32. [35]Alexander GE Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults Neurobiol Aging 2012 33 2723 2732 10.1016/j.neurobiolaging.2012.01.014 22405043 PMC3398228 · DOI
  33. [36]Grienberger C Konnerth A Imaging calcium in neurons Neuron 2012 73 862 885 10.1016/j.neuron.2012.02.011 22405199 · DOI
  34. [38]Tippmann F Hundt J Schneider A Endres K Fahrenholz F Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin FASEB J. 2009 23 1643 1654 10.1096/fj.08-121392 19144697 · DOI
  35. [39]Reinhardt S Rescue of hypovitaminosis a induces non-amyloidogenic amyloid precursor protein (APP) processing Curr. Alzheimer Res 2016 13 1277 1289 10.2174/1567205013666160603002105 27335034 · DOI
  36. [40]Dos Santos Guilherme M The synthetic retinoid acitretin increases IL-6 in the central nervous system of Alzheimer disease model mice and human patients Front. Aging Neurosci. 2019 11 182 10.3389/fnagi.2019.00182 31396076 PMC6664027 · DOI
  37. [41]Holthoewer D Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein Neurodegener. Dis. 2012 10 224 228 10.1159/000334300 22301853 · DOI
  38. [42]Morris RG Anderson E Lynch GS Baudry M Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5 Nature 1986 319 774 776 10.1038/319774a0 2869411 · DOI · Paper page
  39. [43]Reinhardt S Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer's disease hallmarks Sci. Rep. 2018 8 1329 10.1038/s41598-018-19577-7 29358714 PMC5778060 · DOI · Paper page
  40. [45]Stosiek C Garaschuk O Holthoff K Konnerth A In vivo two-photon calcium imaging of neuronal networks Proc. Natl. Acad. Sci. U. S. A.s 2003 100 7319 7324 10.1073/pnas.1232232100 PMC165873 12777621 · DOI
  41. [46]Friedrich J Zhou P Paninski L Fast online deconvolution of calcium imaging data PLoS Comput. Biol. 2017 13 e1005423 10.1371/journal.pcbi.1005423 28291787 PMC5370160 · DOI
  42. [47]Chen L Deng Y Luo W Wang Z Zeng S Detection of bursts in neuronal spike trains by the mean inter-spike interval method Progr. Natl. Sci. 2009 19 229 235 10.1016/j.pnsc.2008.05.027 · DOI
  43. [48]Aerts H Fias W Caeyenberghs K Marinazzo D Brain networks under attack: Robustness properties and the impact of lesions Brain 2016 139 3063 3083 10.1093/brain/aww194 27497487 · DOI
  44. [49]Newman ME Assortative mixing in networks Phys. Rev. Lett. 2002 89 208701 10.1103/PhysRevLett.89.208701 12443515 · DOI
  45. [50]Dogra S Yadav S Acitretin in psoriasis: An evolving scenario Int. J. Dermatol. 2014 53 525 538 10.1111/ijd.12365 24601982 · DOI
  46. [51]Endres K Increased CSF APPs-alpha levels in patients with Alzheimer disease treated with acitretin Neurology 2014 83 1930 1935 10.1212/WNL.0000000000001017 25344383 · DOI
  47. [52]Raji CA Lopez OL Kuller LH Carmichael OT Becker JT Age, Alzheimer disease, and brain structure Neurology 2009 73 1899 1905 10.1212/WNL.0b013e3181c3f293 19846828 PMC2788799 · DOI
  48. [54]Sporns O Structure and function of complex brain networks Dialogues Clin. Neurosci. 2013 15 247 262 10.31887/DCNS.2013.15.3/osporns 24174898 PMC3811098 · DOI
  49. [55]Bonifazi P GABAergic hub neurons orchestrate synchrony in developing hippocampal networks Science 2009 326 1419 1424 10.1126/science.1175509 19965761 · DOI · Paper page
  50. [56]Stringer C Spontaneous behaviors drive multidimensional, brainwide activity Science 2019 364 255 10.1126/science.aav7893 31000656 PMC6525101 · DOI · Paper page
  51. [57]Shimaoka D Harris KD Carandini M Effects of arousal on mouse sensory cortex depend on modality Cell. Rep. 2018 22 3160 3167 10.1016/j.celrep.2018.02.092 29562173 PMC5883328 · DOI
  52. [59]Harris KD Thiele A Cortical state and attention Nat. Rev. Neurosci. 2011 12 509 523 10.1038/nrn3084 21829219 PMC3324821 · DOI
  53. [61]Burgold J Cortical circuit alterations precede motor impairments in Huntington's disease mice Sci. Rep. 2019 9 6634 10.1038/s41598-019-43024-w 31036840 PMC6488584 · DOI
  54. [62]Koukouli F Rooy M Maskos U Early and progressive deficit of neuronal activity patterns in a model of local amyloid pathology in mouse prefrontal cortex Aging (Albany NY) 2016 8 3430 3449 10.18632/aging.101136 27999185 PMC5270678 · DOI
  55. [63]Reinhardt S Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease FASEB J 2014 28 978 997 10.1096/fj.13-234864 24165480 · DOI
  56. [64]del Rey A Balschun D Wetzel W Randolf A Besedovsky HO A cytokine network involving brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and TNFalpha operates during long-term potentiation and learning Brain Behav. Immunol. 2013 33 15 23 10.1016/j.bbi.2013.05.011 23747799 · DOI
  57. [65]Dos Santos Guilherme M Dietary wheat amylase trypsin inhibitors impact Alzheimer's disease pathology in 5xFAD model mice Int. J. Mol. Sci. 2020 10.3390/ijms21176288 32878020 PMC7503408 · DOI
  58. [66]Parish CL The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice J. Neurosci. 2002 22 8034 8041 10.1523/jneurosci.22-18-08034.2002 12223557 PMC6758077 · DOI
  59. [67]Armstrong JL Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells Br. J. Cancer 2005 92 696 704 10.1038/sj.bjc.6602398 15714209 PMC2361877 · DOI
  60. [68]Avraham Y Beta-carotene as a novel therapy for the treatment of "Autistic like behavior" in animal models of Autism Behav. Brain Res. 2017 10.1016/j.bbr.2017.09.041 28963040 · DOI
  61. [69]Zhong LR Chen X Park E Südhof TC Chen L Retinoic acid receptor RARα-dependent synaptic signaling mediates homeostatic synaptic plasticity at the inhibitory synapses of mouse visual cortex J. Neurosci. 2018 38 10454 10466 10.1523/JNEUROSCI.1133-18.2018 30355624 PMC6284108 · DOI
  62. [70]Haghikia A Long-term potentiation in the visual cortex requires both nitric oxide receptor guanylyl cyclases J. Neurosci. 2007 27 818 823 10.1523/JNEUROSCI.4706-06.2007 17251421 PMC6672906 · DOI
  63. [71]Kurauchi Y Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF J. Neurochem. 2011 116 323 333 10.1111/j.1471-4159.2010.06916.x 20649843 · DOI
  64. [72]Jiang B Brain-derived neurotrophic factor acutely depresses excitatory synaptic transmission to GABAergic neurons in visual cortical slices Eur. J. Neurosci. 2004 20 709 718 10.1111/j.1460-9568.2004.03523.x 15255981 · DOI
  65. [73]Palizvan MR Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex Neuroscience 2004 126 955 966 10.1016/j.neuroscience.2004.03.053 15207329 · DOI
  66. [74]Criscuolo C Entorhinal cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model Sci. Rep. 2017 7 42370 10.1038/srep42370 28205565 PMC5304222 · DOI
  67. [75]Nakazono T Impaired Front. Syst. Neurosci. 2017 11 48 10.3389/fnsys.2017.00048 28713250 PMC5491963 · DOI
  68. [76]Hendel T Fluorescence changes of genetic calcium indicators and OGB-1 correlated with neural activity and calcium in vivo and in vitro J. Neurosci. 2008 28 7399 7411 10.1523/JNEUROSCI.1038-08.2008 18632944 PMC6670390 · DOI
  69. [77]Rochefort NL Sparsification of neuronal activity in the visual cortex at eye-opening Proc. Natl. Acad. Sci. U. S. A. 2009 106 15049 15054 10.1073/pnas.0907660106 19706480 PMC2736444 · DOI
  70. [78]Yaksi E Friedrich RW Reconstruction of firing rate changes across neuronal populations by temporally deconvolved Ca2+ imaging Nat. Methods 2006 3 377 383 10.1038/nmeth874 16628208 · DOI
  71. [79]Vogelstein JT Spike inference from calcium imaging using sequential Monte Carlo methods Biophys. J. 2009 97 636 655 10.1016/j.bpj.2008.08.005 19619479 PMC2711341 · DOI
  72. [80]Akerboom J Optimization of a GCaMP calcium indicator for neural activity imaging J. Neurosci. 2012 32 13819 13840 10.1523/JNEUROSCI.2601-12.2012 23035093 PMC3482105 · DOI
  73. [81]Chen TW Ultrasensitive fluorescent proteins for imaging neuronal activity Nature 2013 499 295 300 10.1038/nature12354 23868258 PMC3777791 · DOI · Paper page
  74. [82]Hires SA Tian L Looger LL Reporting neural activity with genetically encoded calcium indicators Brain Cell. Biol. 2008 36 69 86 10.1007/s11068-008-9029-4 18941901 PMC2755531 · DOI

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Authors
Rosales Jubal, E., Schwalm, M., dos Santos Guilherme, M., Schuck, F., Reinhardt, S., Tose, A., Barger, Z., Roesler, M. K., Ruffini, N., Wierczeiko, A., Schmeisser, M. J., Schmitt, U., Endres, K., & Stroh, A.
Affiliations
  • Goethe University Frankfurt (DE)
  • Johannes Gutenberg University Mainz (DE)
  • Leibniz Institute for Resilience Research (DE)
Corresponding author
Stroh, Albrecht
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2021-03-23
Volume
11
Issue
1
Pages
6649-6649
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-021-85912-0
PMC
PMC7988040
OpenAlex
W3136051851
Cited by
30
References
8
Citations by year
2026: 5 · 2025: 2 · 2024: 10 · 2023: 7 · 2022: 3 · 2021: 3
FWCI
3.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Gutenberg Open Science (submittedVersion, cc-by-nd)
  • Gutenberg Open Science (cc-by)
Funders
  • Alfred Dollwet Foundation
  • Focus Program Translational Neurosciences
  • Boehringer Ingelheim Foundation
  • Stiftung Rheinland-Pfalz für Innovation
  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
acitretin, familial Alzheimer's disease, 5xFAD mice, cortical microcircuits, spontaneous neuronal activity, burstiness, network topology, graph theory, network robustness, excitatory synapses, amyloid plaques, early diagnosis
MeSH terms
Alzheimer Disease, Animals, Brain, Calcium, Disease Models, Animal, Humans, Immunohistochemistry, Neural Pathways, Neurons, Synapses, Amyloid beta-Peptides, Acitretin, Mice, Plaque, Amyloid, Brain Waves, Optical Imaging, Protein Aggregation, Pathological

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