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Oncotarget. 2017 Apr 22;8(39):64745-64778. doi: 10.18632/oncotarget.17371. eCollection 2017 Sep 12.

Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer's disease and other tauopathies.

Author information

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.

Abstract

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 NH2 tau 26-44 (aka NH 2 htau) -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 NH 2 htau. 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.

KEYWORDS:

Alzheimer’s disease; Gerotarget; extracellular tau; neurodegeneration; synapse(s); tau cleavage

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no actual or potential conflicts of interest and that these data are not published elsewhere. In addition all authors approve the study described in this report.

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