Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2017 Jan 27

PMID 28123067

Citations 219

Authors

Sarah L DeVos

Rebecca L Miller

Kathleen M Schoch

Brandon B Holmes

Carey S Kebodeaux

Amy J Wegener

Guo Chen

Tao Shen

Hien Tran

Brandon Nichols

Tom A Zanardi

Holly B Kordasiewicz

Eric E Swayze

C Frank Bennett

Marc I Diamond

Timothy M Miller

Affiliations

Soon will be listed here.

Abstract

Accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer's disease and other primary tauopathies. One therapeutic strategy may be to reduce total tau expression. We identified antisense oligonucleotides (ASOs) that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and preexisting phosphorylated tau and Thioflavin S pathology were reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In addition, mouse survival was extended, and pathological tau seeding was reversed. In nonhuman primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid. These data support investigation of a tau-lowering therapy in human patients who have tau-positive inclusions even after pathological tau deposition has begun.

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References

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H . Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013; 110(47):E4530-9. PMC: 3839752. DOI: 10.1073/pnas.1318835110. View

Goedert M, Ghetti B, Spillantini M . Frontotemporal dementia: implications for understanding Alzheimer disease. Cold Spring Harb Perspect Med. 2012; 2(2):a006254. PMC: 3281593. DOI: 10.1101/cshperspect.a006254. View

Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson P, Dewar K . The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathol. 2012; 124(5):693-704. PMC: 3608475. DOI: 10.1007/s00401-012-1017-1. View

Sanders D, Kaufman S, DeVos S, Sharma A, Mirbaha H, Li A . Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014; 82(6):1271-88. PMC: 4171396. DOI: 10.1016/j.neuron.2014.04.047. View

Takeda S, Commins C, DeVos S, Nobuhara C, Wegmann S, Roe A . Seed-competent high-molecular-weight tau species accumulates in the cerebrospinal fluid of Alzheimer's disease mouse model and human patients. Ann Neurol. 2016; 80(3):355-67. PMC: 5016222. DOI: 10.1002/ana.24716. View

Saul A, Sprenger F, Bayer T, Wirths O . Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease. Neurobiol Aging. 2013; 34(11):2564-73. DOI: 10.1016/j.neurobiolaging.2013.05.003. View

Myeku N, Clelland C, Emrani S, Kukushkin N, Yu W, Goldberg A . Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med. 2015; 22(1):46-53. PMC: 4787271. DOI: 10.1038/nm.4011. View

Polydoro M, de Calignon A, Suarez-Calvet M, Sanchez L, Kay K, Nicholls S . Reversal of neurofibrillary tangles and tau-associated phenotype in the rTgTauEC model of early Alzheimer's disease. J Neurosci. 2013; 33(33):13300-11. PMC: 3742920. DOI: 10.1523/JNEUROSCI.0881-13.2013. View

Liu L, Drouet V, Wu J, Witter M, Small S, Clelland C . Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012; 7(2):e31302. PMC: 3270029. DOI: 10.1371/journal.pone.0031302. View

10.

Morris M, Hamto P, Adame A, Devidze N, Masliah E, Mucke L . Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice. Neurobiol Aging. 2013; 34(6):1523-9. PMC: 3596503. DOI: 10.1016/j.neurobiolaging.2012.12.003. View

11.

Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen C . Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015; 523(7561):431-436. PMC: 4718588. DOI: 10.1038/nature14658. View

12.

van Hummel A, Bi M, Ippati S, van der Hoven J, Volkerling A, Lee W . No Overt Deficits in Aged Tau-Deficient C57Bl/6.Mapttm1(EGFP)Kit GFP Knockin Mice. PLoS One. 2016; 11(10):e0163236. PMC: 5063411. DOI: 10.1371/journal.pone.0163236. View

13.

Nelson P, Alafuzoff I, Bigio E, Bouras C, Braak H, Cairns N . Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012; 71(5):362-81. PMC: 3560290. DOI: 10.1097/NEN.0b013e31825018f7. View

14.

Zhao Y, Tseng I, Heyser C, Rockenstein E, Mante M, Adame A . Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron. 2015; 87(5):963-75. PMC: 4575284. DOI: 10.1016/j.neuron.2015.08.020. View

15.

McKay R, Miraglia L, Cummins L, Owens S, Sasmor H, Dean N . Characterization of a potent and specific class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression. J Biol Chem. 1999; 274(3):1715-22. DOI: 10.1074/jbc.274.3.1715. View

16.

DeVos S, Goncharoff D, Chen G, Kebodeaux C, Yamada K, Stewart F . Antisense reduction of tau in adult mice protects against seizures. J Neurosci. 2013; 33(31):12887-97. PMC: 3728694. DOI: 10.1523/JNEUROSCI.2107-13.2013. View

17.

Li Z, Hall A, Kelinske M, Roberson E . Seizure resistance without parkinsonism in aged mice after tau reduction. Neurobiol Aging. 2014; 35(11):2617-2624. PMC: 4171213. DOI: 10.1016/j.neurobiolaging.2014.05.001. View

18.

Donnelly C, Zhang P, Pham J, Haeusler A, Heusler A, Mistry N . RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013; 80(2):415-28. PMC: 4098943. DOI: 10.1016/j.neuron.2013.10.015. View

19.

Min S, Chen X, Tracy T, Li Y, Zhou Y, Wang C . Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015; 21(10):1154-62. PMC: 4598295. DOI: 10.1038/nm.3951. View

20.

Bi M, Ittner A, Ke Y, Gotz J, Ittner L . Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS One. 2011; 6(12):e26860. PMC: 3234245. DOI: 10.1371/journal.pone.0026860. View