Amelioration of Tau pathology and memory deficits by targeting 5-HT7 receptor

• Published in: Progress in neurobiology 2021-02, Vol.197, p.101900, Article 101900
• Main Authors: Labus, Josephine, Röhrs, Kian-Fritz, Ackmann, Jana, Varbanov, Hristo, Müller, Franziska E., Jia, Shaobo, Jahreis, Kathrin, Vollbrecht, Anna-Lena, Butzlaff, Malte, Schill, Yvonne, Guseva, Daria, Böhm, Katrin, Kaushik, Rahul, Bijata, Monika, Marin, Philippe, Chaumont-Dubel, Séverine, Zeug, Andre, Dityatev, Alexander, Ponimaskin, Evgeni
• Format: Article
• Language: English
• Subjects: 5-HT7 receptor; Animals; CDK5; Dementia; Disease Models, Animal; Life Sciences; Long-Term Potentiation; Memory Disorders; Mice; Neurons and Cognition; Receptors, Serotonin - genetics; Serotonin; tau Proteins; Tauopathies
• ISSN: 0301-0082; 1873-5118
• DOI: 10.1016/j.pneurobio.2020.101900

•Constitutive 5-HT7R activity rises pathological Tau phosphorylation and aggregation.•5-HT7R modulates Tau phosphorylation via CDK5 in Gprotein-independent manner.•5-HT7R/CDK5/Tau signaling leads to neuronal death and impaired memory in mice.•Blockade of constitutive 5-HT7R activity prevents Tau aggregation and neurotoxicity.•5-HT7R knockdown abrogates Tau[R406W]-induced LTP deficits and memory impairments. Tauopathies comprise a heterogeneous family of neurodegenerative diseases characterized by pathological accumulation of hyperphosphorylated Tau protein. Pathological changes in serotonergic signaling have been associated with tauopathy etiology, but the underlying mechanisms remain poorly understood. Here, we studied the role of the serotonin receptor 7 (5-HT7R), in a mouse model of tauopathy induced by overexpressing the human Tau[R406W] mutant associated with inherited forms of frontotemporal dementia. We showed that the constitutive 5-HT7R activity is required for Tau hyperphosphorylation and formation of highly bundled Tau structures (HBTS) through G-protein-independent, CDK5-dependent mechanism. We also showed that 5-HT7R physically interacts with CDK5. At the systemic level, 5-HT7R-mediated CDK5 activation induces HBTS leading to neuronal death, reduced long-term potentiation (LTP), and impaired memory in mice. Specific blockade of constitutive 5-HT7R activity in neurons that overexpressed Tau[R406W] prevents Tau hyperphosphorylation, aggregation, and neurotoxicity. Moreover, 5-HT7R knockdown in the prefrontal cortex fully abrogates Tau[R406W]-induced LTP deficits and memory impairments. Thus, 5-HT7R/CDK5 signaling emerged as a new, promising target for tauopathy treatments.