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

Affiliation

Labus J(1), Röhrs KF(2), Ackmann J(1), Varbanov H(3), Müller FE(1), Jia S(4), Jahreis K(1), Vollbrecht AL(1), Butzlaff M(1), Schill Y(1), Guseva D(1), Böhm K(4), Kaushik R(5), Bijata M(6), Marin P(7), Chaumont-Dubel S(7), Zeug A(1), Dityatev A(8), Ponimaskin E(9).
Author information:
(1)Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany.
(2)Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany; Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
(3)Instituite of Neurophysiology, Hannover Medical School, Hannover, Germany; German Center for Neurodegenerative Diseases
(DZNE), Magdeburg, Germany.
(4)German Center for Neurodegenerative Diseases
(DZNE), Magdeburg, Germany.
(5)German Center for Neurodegenerative Diseases
(DZNE), Magdeburg, Germany; Center for Behavioral Brain Sciences
(CBBS), Magdeburg, Germany.
(6)Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany; Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Science, Warsaw, Poland.
(7)IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France.
(8)German Center for Neurodegenerative Diseases
(DZNE), Magdeburg, Germany; Center for Behavioral Brain Sciences
(CBBS), Magdeburg, Germany; Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. Electronic address: [Email]
(9)Department of Cellular Neurophysiology, Hannover Medical School, Hannover, Germany; Institute of Neuroscience, Lobachevsky State University of Nizhni Novgorod, Russia. Electronic address: [Email]

Abstract

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.