Characteristics and consequences of muscarinic receptor activation by tau protein Alberto Gómez-Ramos a,c,1 , Miguel Díaz-Hernández b,1 , Alicia Rubio a,c , Juan Ignacio Díaz-Hernández b , Maria Teresa Miras-Portugal b , Jesus Avila a,c, ⁎ a Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain b Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain c CIBERNED, Spanish Ministry of Health, Spain Received 25 February 2009; received in revised form 25 March 2009; accepted 7 April 2009 KEYWORDS Tau protein; Alzheimer; Muscarinic receptors Abstract It was recently suggested that tau protein released as a result of neuronal death is toxic to neighbouring cells, an effect that is mediated through the activation of muscarinic M1 and/or M3 receptors. Nevertheless, why tau protein and not other native muscarinic agonists, like ACh, can induce this neurotoxicity remains unknown. To clarify this issue, we analysed the different responses and properties of muscarinic receptors in response to stimulation by tau or ACh. The results revealed that the tau protein has an affinity for muscarinic receptors of around one order of magnitude higher than that of ACh. Furthermore, while the repeated stimulation with ACh induces desensitization of the muscarinic receptors, reiterate stimulation with tau failed to produce this phenomenon. Finally, we found the tau protein to be very stable in the extracellular milieu. These studies provide valuable information to help understand tau toxicity on neural cells bearing M1 or M3 muscarinic receptors and its contribution to neurodegenerative progression in tauopathies. © 2009 Elsevier B.V. and ECNP. All rights reserved. 1. Introduction Alzheimer's disease (AD) is characterized by both the occurrence of neuronal death in the brain of patients together with the appearance of two aberrant structures: senile plaques (SP) and intracellular neurofibrillary tangles (NFT). There is a good correlation between neurofibrillary pathology and nerve cell degeneration (Arriagada et al., 1992) and as a consequence of neuron death, intracellular neurofibrillary lesions can reach the extracellular space as ghost tangles. Indeed, in damaged regions like the hippocampus, an inverse correlation between the number of ghost tangles and the number of surviving nerve cells is evident (Bondareff et al., 1989; Cras et al., 1995; Fukutani et al., 1995). The development of neurofibrillary lesions correlates with the progress of the disease from the entorhinal cortex to the hippocampal region, and from there to the cortex (Braak and Braak, 1991). The main component of the NFT is the hyperphosphorylated form of the microtubule associated ⁎ Corresponding author. Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain. Tel.: +34 911964564; fax: +34 911964420. E-mail address: javila@cbm.uam.es (J. Avila). 1 These authors contributed equally to this work. 0924-977X/$ - see front matter © 2009 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2009.04.006 www.elsevier.com/locate/euroneuro European Neuropsychopharmacology (2009) 19, 708–717