Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy

• Published in: Progress in neurobiology 2020-03, Vol.186, p.101743, Article 101743
• Main Authors: Rossi, Daniela, Gruart, Agnès, Contreras-Murillo, Gerardo, Muhaisen, Ashraf, Ávila, Jesús, Delgado-García, José María, Pujadas, Lluís, Soriano, Eduardo
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer’s disease; Animals; Avoidance Learning - physiology; Behavior, Animal - physiology; Cell Adhesion Molecules, Neuronal - metabolism; Cognition; Disease Models, Animal; Electrophysiology; Extracellular Matrix Proteins - metabolism; Intracellular signaling; Long-Term Potentiation - physiology; Memory, Long-Term - physiology; Mice; Mice, Transgenic; Nerve Tissue Proteins - metabolism; Reelin; Serine Endopeptidases - metabolism; Signal Transduction - physiology; tau Proteins - metabolism; Tauopathies - metabolism; Tauopathies - physiopathology; Tauopathy
• ISSN: 0301-0082; 1873-5118
• DOI: 10.1016/j.pneurobio.2019.101743

•Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in the VLW mouse model of Tauopathy, overexpressing a Tauopathy-related mutated form of human Tau.•In vitro, Reelin rescues the Aβ-induced missorting of axonal proteins such as neurofilaments (NF) and Tau to the somatodendritic compartment, which is one of the earliest events in Tau pathology.•Reelin reverts in vivo the toxic somatodendritic localization of phosphorylated Tau in CA1/CA3 dendrites in VLW mice, as well as in the cell bodies of the granular layer in the VLW model.•Overexpression of Reelin in the VLW model improves physiological long-term potentiation and long-term memory cognitive performance in the passive avoidance paradigm, thus masking the cognitive and physiological deficits associated with the VLW genotype. Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-β (Aβ) pathology in Alzheimer’s Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aβ-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aβ pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.