CoChat
Sign Up
Cited by 29Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Ablating Tau Reduces Hyperexcitability and Moderates Electroencephalographic Slowing in Transgenic Mice Expressing A53T Human α-Synuclein

Open access
Peters, Samuel T., Fahrenkopf, Allyssa, Choquette, Jessica M., Vermilyea, Scott C., Lee, Michael K., Vossel, Keith·2020·Frontiers in Neurology
DOI 10.3389/fneur.2020.00563PMC PMC7316964
Open this paper in CoChat — free accountOpen PDF

Abstract

Abnormal intraneuronal accumulation of the presynaptic protein α-synuclein (α-syn) is implicated in the etiology of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Recent work revealed that mice expressing human α-syn with the alanine-53-threonine (A53T) mutation have a similar phenotype to the human condition, exhibiting long-term potentiation deficits, learning and memory deficits, and inhibitory hippocampal remodeling, all of which were reversed by genetic ablation of microtubule-associated protein tau. Significantly, memory deficits were associated with histological signs of network hyperactivity/seizures. Electrophysiological abnormalities are often seen in parkinsonian dementias. Baseline electroencephalogram (EEG) slowing is used as a supportive diagnostic feature in DLB and PDD, and patients with these diseases may exhibit indicators of broad network dysfunction such as sleep dysregulation, myoclonus, and seizures. Given the translational significance, we examined whether human A53T α-syn expressing mice exhibit endogenous-tau-dependent EEG abnormalities, as measured with epidural electrodes over the frontal and parietal cortices. Using template-based waveform sorting, we determined that A53T mice have significantly high numbers of epileptiform events as early as 3-4 months of age and throughout life, and this effect is markedly attenuated in the absence of tau. Epileptic myoclonus occurred in half of A53T mice and was markedly reduced by tau ablation. In spectral analysis, tau ablation partially reduced EEG slowing in 6-7 month transgenic mice. We found abnormal sleeping patterns in transgenic mice that were more pronounced in older groups, but did not find evidence that this was influenced by tau genotype. Together, these data support the notion that tau facilitates A53T α-syn-induced hyperexcitability that both precedes and coincides with associated synaptic, cognitive, and behavioral effects. Tau also contributes to some aspects of EEG slowing in A53T mice. Importantly, our work supports tau-based approaches as an effective early intervention in α-synucleinopathies to treat aberrant network activity.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fneur.2020.00563

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 50

  1. [2]Vossel KA Beagle AJ Rabinovici GD Shu H Lee SE Naasan G. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. (2013) 70: 1158– 66. 10.1001/jamaneurol.2013.136 23835471 PMC4013391 · DOI
  2. [3]Baker J Libretto T Henley W Zeman A. A longitudinal study of epileptic seizures in Alzheimer's disease. Front Neurol. (2019) 10: 1266. 10.3389/fneur.2019.01266 31866927 PMC6904279 · DOI
  3. [4]Vossel KA Ranasinghe KG Beagle AJ Mizuiri D Honma SM Dowling AF. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann Neurol. (2016) 80: 858– 70. 10.1002/ana.24794 27696483 PMC5177487 · DOI · Paper page
  4. [5]Caviness JN Adler CH Newman S Caselli RJ Muenter MD. Cortical myoclonus in levodopa-responsive parkinsonism. Mov Disord. (1998) 13: 540– 4. 10.1002/mds.870130327 9613750 · DOI
  5. [6]Spira PJ Sharpe DM Halliday G Cavanagh J Nicholson GA. Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr α-synuclein mutation. Ann Neurol. (2001) 49: 313– 9. 10.1002/ana.67 11261505 · DOI
  6. [7]Caviness JN Gwinn-Hardy K Adler CH Muenter MD. Electrophysiological observations in hereditary parkinsonism-dementia with Lewy body pathology. Mov Disord. (2000) 15: 140– 5. 10.1002/1531-8257(200001)15:1<140::aid-mds1022>3.0.co;2-5 10634254 · DOI
  7. [8]Kam K Duffy AM Moretto J LaFrancois JJ Scharfman HE. Interictal spikes during sleep are an early defect in the Tg2576 mouse model of beta-amyloid neuropathology. Sci Rep. (2016) 6: 20119. 10.1038/srep20119 26818394 PMC4730189 · DOI
  8. [10]Sanchez PE Zhu L Verret L Vossel KA Orr AG Cirrito JR. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci USA. (2012) 109: E2895– 903. 10.1073/pnas.1121081109 22869752 PMC3479491 · DOI · Paper page
  9. [11]Morris M Sanchez PE Verret L Beagle AJ Guo W Dubal D. Network dysfunction in alpha-synuclein transgenic mice and human Lewy body dementia. Ann Clin Transl Neurol. (2015) 2: 1012– 28. 10.1002/acn3.257 26732627 PMC4693622 · DOI · Paper page
  10. [12]McKeith I Mintzer J Aarsland D Burn D Chiu H Cohen-Mansfield J Dementia with Lewy bodies. Lancet Neurol. (2004) 3: 19– 28. 10.1016/s1474-4422(03)00619-7 14693108 · DOI
  11. [13]McKeith IG Dickson DW Lowe J Emre M O'Brien JT Feldman H. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. (2005) 65: 1863– 72. 10.1212/01.wnl.0000187889.17253.b1 16237129 · DOI · Paper page
  12. [14]Briel RC McKeith IG Barker WA Hewitt Y Perry RH Ince PG. EEG findings in dementia with Lewy bodies and Alzheimer's disease. J Neurol Neurosurg Psychiatry. (1999) 66: 401– 3. 10.1136/jnnp.66.3.401 10084544 PMC1736269 · DOI
  13. [15]Sales-Carbonell C Rueda-Orozco PE Soria-Gomez E Buzsaki G Marsicano G Robbe D. Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony. Proc Natl Acad Sci USA. (2013) 110: 719– 24. 10.1073/pnas.1217144110 23269835 PMC3545808 · DOI
  14. [16]Brooks PL Peever JH. Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice. J Neurosci. (2011) 31: 7111– 21. 10.1523/jneurosci.0347-11.2011 21562273 PMC6703223 · DOI
  15. [17]Larsen KE Schmitz Y Troyer MD Mosharov E Dietrich P Quazi AZ. Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci. (2006) 26: 11915– 22. 10.1523/jneurosci.3821-06.2006 17108165 PMC6674868 · DOI
  16. [19]Polymeropoulos MH Lavedan C Leroy E Ide SE Dehejia A Dutra A. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. (1997) 276: 2045– 7. 10.1126/science.276.5321.2045 9197268 · DOI · Paper page
  17. [20]Appel-Cresswell S Vilarino-Guell C Encarnacion M Sherman H Yu I Shah B. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord. (2013) 28: 811– 3. 10.1002/mds.25421 23457019 · DOI
  18. [21]Zarranz JJ Alegre J Gomez-Esteban JC Lezcano E Ros R Ampuero I. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. (2004) 55: 164– 73. 10.1002/ana.10795 14755719 · DOI · Paper page
  19. [22]Krüger R Kuhn W Müller T Woitalla D Graeber M Kösel S. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat Genet. (1998) 18: 106– 8. 10.1038/ng0298-106 9462735 · DOI · Paper page
  20. [23]Ross OA Braithwaite AT Skipper LM Kachergus J Hulihan MM Middleton FA. Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann Neurol. (2008) 63: 743– 50. 10.1002/ana.21380 18571778 PMC3850281 · DOI
  21. [24]Duda JE Giasson BI Mabon ME Miller DC Golbe LI Lee VM. Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol. (2002) 104: 7– 11. 10.1007/s00401-002-0563-3 12070658 · DOI
  22. [25]Teravskis PJ Covelo A Miller EC Singh B Martell-Martinez HA Benneyworth MA. A53T mutant alpha-synuclein induces tau-dependent postsynaptic impairment independently of neurodegenerative changes. J Neurosci. (2018) 38: 9754– 67. 10.1523/jneurosci.0344-18.2018 30249789 PMC6222065 · DOI
  23. [26]Lee MK Stirling W Xu Y Xu X Qui D Mandir AS. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 –> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA. (2002) 99: 8968– 73. 10.1073/pnas.132197599 12084935 PMC124407 · DOI · Paper page
  24. [27]Singh B Covelo A Martell-Martinez H Nanclares C Sherman MA Okematti E. Tau is required for progressive synaptic and memory deficits in a transgenic mouse model of alpha-synucleinopathy. Acta Neuropathol. (2019) 138: 551– 74. 10.1007/s00401-019-02032-w 31168644 PMC6778173 · DOI
  25. [28]Barone P Morelli M Cicarelli G Cozzolino A DeJoanna G Campanella G. Expression of c-fos protein in the experimental epilepsy induced by pilocarpine. Synapse. (1993) 14: 1– 9. 10.1002/syn.890140102 8511714 · DOI
  26. [29]Nägerl UV Mody I Jeub M Lie AA Elger CE Beck H. Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy. J Neurosci. (2000) 20: 1831– 6. 10.1523/jneurosci.20-05-01831.2000 10684884 PMC6772910 · DOI
  27. [30]Palop JJ Chin J Roberson ED Wang J Thwin MT Bien-Ly N. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. (2007) 55: 697– 711. 10.1016/j.neuron.2007.07.025 17785178 PMC8055171 · DOI · Paper page
  28. [31]Tucker KL Meyer M Barde YA. Neurotrophins are required for nerve growth during development. Nat Neurosci. (2001) 4: 29– 37. 10.1038/82868 11135642 · DOI
  29. [32]Tang X Sanford LD. Telemetric recording of sleep and home cage activity in mice. Sleep. (2002) 25: 691– 9. 10.1093/sleep/25.6.677 12224849 · DOI
  30. [33]Morrow JD Opp MR. Sleep-wake behavior and responses of interleukin-6-deficient mice to sleep deprivation. Brain Behav Immun. (2005) 19: 28– 39. 10.1016/j.bbi.2004.02.003 15581736 · DOI
  31. [34]McDowell KA Shin D Roos KP Chesselet MF. Sleep dysfunction and EEG alterations in mice overexpressing alpha-synuclein. J Parkinsons Dis. (2014) 4: 531– 9. 10.3233/jpd-140374 24867919 PMC5777499 · DOI
  32. [35]Vossel KA Tartaglia MC Nygaard HB Zeman AZ Miller BL. Epileptic activity in Alzheimer's disease: causes and clinical relevance. Lancet Neurol. (2017) 16: 311– 22. 10.1016/s1474-4422(17)30044-3 28327340 PMC5973551 · DOI · Paper page
  33. [36]Bonanni L Thomas A Tiraboschi P Perfetti B Varanese S Onofrj M. EEG comparisons in early Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease with dementia patients with a 2-year follow-up. Brain. (2008) 131: 690– 705. 10.1093/brain/awm322 18202105 · DOI
  34. [37]Roberson ED Scearce-Levie K Palop JJ Yan F Cheng IH Wu T. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. (2007) 316: 750– 4. 10.1126/science.1141736 17478722 · DOI · Paper page
  35. [38]Roberson ED Halabisky B Yoo JW Yao J Chin J Yan F. Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. (2011) 31: 700– 11. 10.1523/jneurosci.4152-10.2011 21228179 PMC3325794 · DOI · Paper page
  36. [39]Ittner LM Ke YD Delerue F Bi M Gladbach A van Eersel J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. (2010) 142: 387– 97. 10.1016/j.cell.2010.06.036 20655099 · DOI · Paper page
  37. [40]Hoover BR Reed MN Su J Penrod RD Kotilinek LA Grant MK. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. (2010) 68: 1067– 81. 10.1016/j.neuron.2010.11.030 21172610 PMC3026458 · DOI · Paper page
  38. [41]Miller EC Teravskis PJ Dummer BW Zhao X Huganir RL Liao D. Tau phosphorylation and tau mislocalization mediate soluble Abeta oligomer-induced AMPA glutamate receptor signaling deficits. Eur J Neurosci. (2014) 39: 1214– 24. 10.1111/ejn.12507 24713000 PMC4123852 · DOI · Paper page
  39. [42]Wills J Credle J Haggerty T Lee JH Oaks AW Sidhu A. Tauopathic changes in the striatum of A53T alpha-synuclein mutant mouse model of Parkinson's disease. PLoS ONE. (2011) 6: e17953. 10.1371/journal.pone.0017953 21445308 PMC3061878 · DOI
  40. [43]Credle JJ George JL Wills J Duka V Shah K Lee YC. GSK-3β dysregulation contributes to Parkinson's-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein. Cell Death Differen. (2015) 22: 838– 51. 10.1038/cdd.2014.179 25394490 PMC4392080 · DOI
  41. [44]Babiloni C Cassetta E Binetti G Tombini M Del Percio C Ferreri F. Resting EEG sources correlate with attentional span in mild cognitive impairment and Alzheimer's disease. Eur J Neurosci. (2007) 25: 3742– 57. 10.1111/j.1460-9568.2007.05601.x 17610594 · DOI
  42. [45]Stomrud E Hansson O Minthon L Blennow K Rosén I Londos E. Slowing of EEG correlates with CSF biomarkers and reduced cognitive speed in elderly with normal cognition over 4 years. Neurobiol Aging. (2010) 31: 215– 23. 10.1016/j.neurobiolaging.2008.03.025 18462837 · DOI
  43. [46]Adler CH Thorpy MJ. Sleep issues in Parkinson's disease. Neurology. (2005) 64(12 suppl 3): S12– S20. 10.1212/WNL.64.12_suppl_3.S12 15994219 · DOI
  44. [47]Rothman SM Griffioen KJ Vranis N Ladenheim B Cong WN Cadet JL. Neuronal expression of familial Parkinson's disease A53T alpha-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice. J Parkinsons Dis. (2013) 3: 215– 29. 10.3233/jpd-120130 23938351 · DOI
  45. [48]Rothman SM Mattson MP. Sleep disturbances in Alzheimer and Parkinson's diseases. Neuromol Med. (2012) 14: 194– 204. 10.1007/s12017-012-8181-2 22552887 PMC4544709 · DOI · Paper page
  46. [49]Graham DR Sidhu A. Mice expressing the A53T mutant form of human alpha-synuclein exhibit hyperactivity and reduced anxiety-like behavior. J Neurosci Res. (2010) 88: 1777– 83. 10.1002/jnr.22331 20077428 PMC2861296 · DOI
  47. [50]Unger EL Eve DJ Perez XA Reichenbach DK Xu Y Lee MK. Locomotor hyperactivity and alterations in dopamine neurotransmission are associated with overexpression of A53T mutant human alpha-synuclein in mice. Neurobiol Dis. (2006) 21: 431– 43. 10.1016/j.nbd.2005.08.005 16230020 · DOI
  48. [51]Zhuang X Oosting RS Jones SR Gainetdinov RR Miller GW Caron MG. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci USA. (2001) 98: 1982– 7. 10.1073/pnas.98.4.1982 11172062 PMC29368 · DOI
  49. [52]Frauscher B von Ellenrieder N Dubeau F Gotman J. EEG desynchronization during phasic REM sleep suppresses interictal epileptic activity in humans. Epilepsia. (2016) 57: 879– 88. 10.1111/epi.13389 27112123 PMC4949560 · DOI
  50. [53]Campana C Zubler F Gibbs S de Carli F Proserpio P Rubino A. Suppression of interictal spikes during phasic rapid eye movement sleep: a quantitative stereo-electroencephalography study. J Sleep Res. (2017) 26: 606– 13. 10.1111/jsr.12533 28401614 · DOI

Cited by

Sorted by citations

Authors
Peters, S. T., Fahrenkopf, A., Choquette, J. M., Vermilyea, S. C., Lee, M. K., & Vossel, K.
Affiliations
University of Minnesota (US)
Corresponding author
Vossel, Keith
ORCID
Venue
Frontiers in Neurology
Publisher
Frontiers Media SA
Published
2020-06-19
Volume
11
Pages
563-563
ISSN
1664-2295 (ISSN-L)
DOI
10.3389/fneur.2020.00563
PMC
PMC7316964
OpenAlex
W3036330626
Cited by
29
References
3
Citations by year
2026: 5 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 2 · 2020: 2
FWCI
1.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neurology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01-108686, R01-AG044342, R01-AG05882, R01-NS086074, R01-NS092093, R56-NS113549)
  • Coins for Alzheimer's Research Trust
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, A53T mutation, EEG slowing, epileptiform activity, network hyperexcitability, Parkinson's disease dementia, dementia with Lewy bodies, synucleinopathies, sleep patterns, transgenic mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review