Cognitive enhancement, TAU phosphorylation reduction, and neuronal protection by the treatment of an LRRK2 inhibitor in a tauopathy mouse model

NEUROBIOLOGY OF AGING

卷:96

Article

Castro-Sanchez, Sara^2,3  Zaldivar-Diez, Josefa⁴  Luengo, Enrique⁵  Lopez, Manuela G.⁵  Gil, Carmen^1,4  Martinez, Ana^1,4  Lastres-Becker, Isabel^1,2,3 

[1] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[2] Inst Invest Biomed Alberto Sols UAM CSIC, Inst Invest Sanitaria La Paz IdiPaz, Madrid, Spain

[3] Univ Autonoma Madrid, Sch Med, Dept Biochem, Madrid, Spain

[4] Ctr Invest Biol CSIC, Madrid, Spain

[5] Univ Autonoma Madrid, Sch Med, Inst Teofilo Hernando Drug Discovery, Dept Pharmacol, Madrid, Spain

关键词: TAU;    Phospho-TAU;    Neurodegeneration;    Synaptic plasticity;    Tauopathy;    LRRK2;   

DOI  :  10.1016/j.neurobiolaging.2020.09.006

来源: Elsevier

【 摘 要 】

Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase whose activity plays an important role in neurodegenerative diseases. Although mutations in LRRK2 gene are the most common cause of monogenic Parkinson's disease, it has been reported that LRRK2 may promote Tau phosphorylation, increasing its aggregation. Thus, the modulation of LRRK2 activity by small molecules able to inhibit this kinase activity could be an innovative therapeutic strategy for different tauopathies. We examined the therapeutic effects of a new benzothiazole-based LRRK2 inhibitor, known as JZ1.40, in a mouse model of tauopathy. Mice were injected in the right hippocampus with an adeno-associated vector expressing human-TAUP301L and treated daily with JZ1.40 (10 mg/kg, i.p) or vehicle for three weeks. JZ1.40 reaches the brain and modulates RAB10 and Tau phosphorylation at the epitopes modified by LRRK2. Moreover, JZ1.40 treatment ameliorates the cognitive impairment induced by TAUP301L overexpression, which correlates with prevention of granular cell layer degeneration by improving synaptic plasticity. These data show that JZ1.40 is neuroprotective in vivo, which is translated into cognition enhancement. (C) 2020 Elsevier Inc. All rights reserved.

【 授权许可】

Free