Antisense oligonucleotide-based targeting of Tau-tubulin kinase 1 prevents hippocampal accumulation of phosphorylated tau in PS19 tauopathy mice

Acta Neuropathologica Communications

Research

Louis Cafaro¹  Kayo Yukawa¹  Satomi Yamamoto-Mcguire¹  Seiko Ikezu²  Tsuneya Ikezu³  FredrikKamme⁴  Christine Hong⁴ 

[1] Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118, Boston, MA, USA;Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118, Boston, MA, USA;Department of Neuroscience, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118, Boston, MA, USA;Department of Neuroscience, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Regenerative Science Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, 55905, Rochester, MN, USA;Mayo Clinic Alzheimer’s Disease Research Center, 55905, Rochester, MN, USA;Robert and Arlene Kogod Center on Aging, Mayo Clinic, 55905, Rochester, MN, USA;Ionis Pharmaceuticals, 92010, Carlsbad, CA, USA;

关键词: Alzheimer’s disease;    Tau;    TTBK1;    Pathology;    Neurodegenerative;    Tauopathy;    Phosphorylated tau protein;   

DOI  :  10.1186/s40478-023-01661-3

 received in 2023-08-16, accepted in 2023-09-29,  发布年份 2023

来源: Springer

【 摘 要 】

Tau tubulin kinase-1 (TTBK1), a neuron-specific tau kinase, is highly expressed in the entorhinal cortex and hippocampal regions, where early tau pathology evolves in Alzheimer’s disease (AD). The protein expression level of TTBK1 is elevated in the cortex brain tissues with AD patients compared to the control subjects. We therefore hypothesized that antisense oligonucleotide (ASO) based targeting Ttbk1 could prevent the accumulation of phosphorylated tau, thereby delaying the development of tau pathology in AD. Here we show that in vivo administration of ASO targeting mouse Ttbk1 (ASO-Ttbk1) specifically suppressed the expression of Ttbk1 without affecting Ttbk2 expression in the temporal cortex of PS19 tau transgenic mice. Central administration of ASO-Ttbk1 in PS19 mice significantly reduced the expression level of representative phosphor-tau epitopes relevant to AD at 8 weeks post-dose, including pT231, pT181, and pS396 in the sarkosyl soluble and insoluble fractions isolated from hippocampal tissues as determined by ELISA and pS422 in soluble fractions as determined by western blotting. Immunofluorescence demonstrated that ASO-Ttbk1 significantly reduced pS422 phosphorylated tau intensity in mossy fibers region of the dentate gyrus in PS19 mice. RNA-sequence analysis of the temporal cortex tissue revealed significant enrichment of interferon-gamma and complement pathways and increased expression of antigen presenting molecules (Cd86, Cd74, and H2-Aa) in PS19 mice treated with ASO-Ttbk1, suggesting its potential effect on microglial phenotype although neurotoxic effect was absent. These datasuggest that TTBK1 is an attractive therapeutic target to suppress TTBK1 without compromising TTBK2 expression and pathological tau phosphorylation in the early stages of AD.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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