Cannabinoid receptor CB2 ablation protects against TAU induced neurodegeneration

Acta Neuropathologica Communications

J. Merchán-Rubira¹  F. Hernández¹  J. Ávila¹  I. Lastres-Becker²  M. Galán-Ganga²  A. Rábano³  J. L. Lanciego⁴  M. Posada-Ayala⁵  E. Luengo⁶  M. G. Lopez⁶  J. Fernández-Ruiz⁷  C. Rodríguez-Cueto⁷ 

[1] Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Universidad Autónoma de Madrid;Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid (UAM), Spain. Instituto de Investigación Sanitaria La Paz (IdiPaz), Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC;Department of Neuropathology and Tissue Bank, Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III;Department of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra;Faculty of Experimental Sciences, Universidad Francisco de Vitoria;Instituto Teófilo Hernando y Departamento de Farmacología Y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid;Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica Y Biología Molecular, Facultad de Medicina, Universidad Complutense, and Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS);

关键词: TAU;    Cannabinoid receptor;    CB2;    Alzheimer’s disease;    Neurodegeneration;    Neuroinflammation;   

DOI  :  10.1186/s40478-021-01196-5

来源: DOAJ

【 摘 要 】

Abstract Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein, for which there is still no effective treatment. Therefore, new pharmacological targets are being sought, such as elements of the endocannabinoid system (ECS). We analysed the occurrence of changes in the ECS in tauopathies and their implication in the pathogenesis. By integrating gene expression analysis, immunofluorescence, genetic and adeno-associated virus expressing TAU mouse models, we found a TAU-dependent increase in CB2 receptor expression in hippocampal neurons, that occurs as an early event in the pathology and was maintained until late stages. These changes were accompanied by alterations in the endocannabinoid metabolism. Remarkably, CB2 ablation in mice protects from neurodegeneration induced by hTAUP301L overexpression, corroborated at the level of cognitive behaviour, synaptic plasticity, and aggregates of insoluble TAU. At the level of neuroinflammation, the absence of CB2 did not produce significant changes in concordance with a possible neuronal location rather than its classic glial expression in these models. These findings were corroborated in post-mortem samples of patients with Alzheimer’s disease, the most common tauopathy. Our results show that neurons with accumulated TAU induce the expression of the CB2 receptor, which enhances neurodegeneration. These results are important for our understanding of disease mechanisms, providing a novel therapeutic strategy to be investigated in tauopathies.

【 授权许可】

Unknown