Delay-Goyet Philippe, Blanchard Véronique, Schussler Nathalie, Lopez-Grancha Mati, Ménager Jean, Mary Véronique, Sultan Eric, Buzy Armelle, Guillemot Jean-Claude, Stemmelin Jeanne, Bertrand Philippe, Rooney Thomas, Pradier Laurent, Barnéoud Pascal
Neurodegeneration and Pain Unit, Sanofi R&D, Chilly-Mazarin, France.
Disposition, Safety and Animal Research, Sanofi R&D, Montpellier, France.
Alzheimers Dement (N Y). 2016 Nov 3;2(4):267-280. doi: 10.1016/j.trci.2016.10.002. eCollection 2016 Nov.
Tau hyperphosphorylation and neurofibrillary tangles are histopathologic hallmarks of tauopathies. Histamine H3-receptor antagonists have been proposed to reduce tau hyperphosphorylation in preclinical models.
We evaluated the ability of SAR110894, a selective histamine H3-receptor antagonist, to inhibit tau pathology and prevent cognitive deficits in a tau transgenic mouse model (THY-Tau22).
SAR110894 treatment for 6 months (but not 2 weeks) in THY-Tau22 mice decreased both tau hyperphosphorylation at pSer396-pSer404 (AD2 signal) in the hippocampus and the number of AT8 (pSer199/202-Thr205) positive cells in the cortex and decreased the formation of neurofibrillary tangles in the cortex, hippocampus, and amygdala. Macrophage inflammatory protein 1-alpha messenger RNA expression was decreased in the hippocampus. SAR110894 also prevented episodic memory deficits, and this effect was still detected after treatment washout.
Long-term SAR110894 treatment could have potential disease modifying activity in neurodegenerative tauopathies.
tau蛋白过度磷酸化和神经原纤维缠结是tau蛋白病的组织病理学特征。在临床前模型中，组胺H3受体拮抗剂已被提出可减少tau蛋白过度磷酸化。
我们评估了选择性组胺H3受体拮抗剂SAR110894在tau转基因小鼠模型（THY-Tau22）中抑制tau病理并预防认知缺陷的能力。
在THY-Tau22小鼠中，SAR110894治疗6个月（而非2周）可降低海马体中pSer396-pSer404（AD2信号）处的tau蛋白过度磷酸化以及皮质中AT8（pSer199/202-Thr205）阳性细胞的数量，并减少皮质、海马体和杏仁核中神经原纤维缠结的形成。海马体中巨噬细胞炎性蛋白1-α信使核糖核酸表达降低。SAR110894还可预防情景记忆缺陷，且在停药后仍能检测到这种效果。
长期使用SAR110894治疗可能对神经退行性tau蛋白病具有潜在的疾病修饰活性。
