Research Papers: Gerotarget (Focus on Aging):
Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer’s disease and other tauopathies
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Fulvio Florenzano1,*, Corsetti Veronica2,*, Gabriele Ciasca3,*, Maria Teresa Ciotti4, Anna Pittaluga5, Gunedalina Olivero5, Marco Feligioni1,6, Filomena Iannuzzi1, Valentina Latina2, Michele Francesco Maria Sciacca7, Alessandro Sinopoli7, Danilo Milardi7, Giuseppe Pappalardo7, De Spirito Marco3, Massimiliano Papi3, Anna Atlante8,9, Antonella Bobba8,9, Antonella Borreca4, Pietro Calissano1 and Giuseppina Amadoro1,2
1 European Brain Research Institute, Rome, Italy
2 Institute of Translational Pharmacology, CNR, Rome, Italy
3 Institute of Physics, Catholic University of the Sacred Heart, Largo F Vito 1, Rome, Italy
4 Institute of Cellular Biology and Neuroscience, CNR, IRCSS Santa Lucia Foundation, Rome, Italy
5 Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Genoa, Viale Cembrano, Italy
6 Department of Neurorehabilitation Sciences, Casa Cura Policlinico, Milan, Italy
7 Institute of Biostructures and Bioimaging, CNR, Catania, Italy
8 Institute of Biomembranes and Bioenergetics, CNR, Bari, Italy
9 Center of Excellence for Biomedical Research, University of Genoa, Genoa, Viale Benedetto XV, Italy
* These authors have equally contributed to this work
Giuseppina Amadoro, email:
Keywords: extracellular tau, tau cleavage, Alzheimer’s disease, neurodegeneration, synapse(s), Gerotarget
Received: March 07, 2017 Accepted: April 11, 2017 Published: April 22, 2017
The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2-derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer’s disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2tau 26-44 (aka NH2htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+-evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH2htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration.
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