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

The largest part of tau secreted from AD nerve terminals and released in cerebral\r\nspinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting\r\npotential extracellular role(s) of NH2-derived fragments of protein on synaptic\r\ndysfunction underlying neurodegenerative tauopathies, including Alzheimer’s disease\r\n(AD). Here we show that sub-toxic doses of extracellular-applied human NH2tau 26-44\r\n(aka NH2htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide\r\naccumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes\r\npresynaptic deficit in K+-evoked glutamate release on hippocampal synaptosomes\r\nalong with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules\r\nbreakdown, deregulation in presynaptic proteins and loss of mitochondria located at\r\nnerve endings are detected in hippocampal cultures only after prolonged exposure\r\nto NH2htau. The specificity of these biological effects is supported by the lack of\r\nany significant change, either on neuronal activity or on cellular integrity, shown\r\nby administration of its reverse sequence counterpart which behaves as an inactive\r\ncontrol, likely due to a poor conformational flexibility which makes it unable to\r\ndynamically perturb biomembrane-like environments. Our results demonstrate that\r\none of the AD-relevant, soluble and secreted N-terminally truncated tau forms can\r\nearly contribute to pathology outside of neurons causing alterations in synaptic\r\nactivity at presynaptic level, independently of overt neurodegeneration.