ABSTRACT
Extracellular tau promotes an increase in the level of intracellular calcium in cultured neuronal cells. We have found that such increase is impaired in the presence of antagonists of muscarinic receptors. In order to identify the nature of those receptors, we have tested the effect of different specific muscarinic receptor antagonists on tau promoted calcium increase. Our results indicate that the increase does not take place in the presence of antagonists of muscarinic (mainly M1 and M3) receptors. A similar increase in intracellular calcium was found in non-neuronal cells transfected with cDNA of M1 and M3 muscarinic receptors when tau was added. These results suggest that observed effect of tau protein on neuronal (neuroblastoma and primary cultures of hippocampal and cortical neurons) cells is through M1 and M3 muscarinic receptors. Therefore blocking M1 and for M3 receptors, by using specific receptor antagonists, can prevent that tau toxic effect that could take place in tauopathies.
Subject(s)
Calcium/metabolism , Extracellular Fluid/physiology , Intracellular Fluid/metabolism , Neurons/metabolism , Receptor, Muscarinic M1/physiology , Receptor, Muscarinic M3/physiology , tau Proteins/physiology , Amino Acid Sequence , Animals , COS Cells , Cell Line, Tumor , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Chlorocebus aethiops , Hippocampus/cytology , Hippocampus/metabolism , Humans , Molecular Sequence Data , Neuroblastoma/metabolism , Neuroblastoma/pathology , Neurons/physiologyABSTRACT
Sporadic Alzheimer disease (SAD) is the most prevalent neurodegenerative disorder. With the development of new generation DNA sequencing technologies, additional genetic risk factors have been described. Here we used various methods to process DNA sequencing data in order to gain further insight into this important disease. We have sequenced the exomes of brain samples from SAD patients and non-demented controls. Using either method, we found a higher number of single nucleotide variants (SNVs), from SAD patients, in genes present at the X chromosome. Using the most stringent method, we validated these variants by Sanger sequencing. Two of these gene variants, were found in loci related to the ubiquitin pathway (UBE2NL and ATXN3L), previously do not described as genetic risk factors for SAD.
Subject(s)
Alzheimer Disease/genetics , Chromosomes, Human, X , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Chromosome Mapping , Computational Biology/methods , Exome , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Reproducibility of ResultsABSTRACT
The possible link between tau phosphorylation and tau assembly in these neurodegenerative diseases known as tauopathies is described. Additionally, this link is supported by an in vitro experiment showing the higher capacity of phosphotau to assemble in some specific conditions; and, by a recently reported experiment using a tau transgenic mouse model.