TY - JOUR
T1 - Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer’s disease and other tauopathies
AU - Florenzano, Fulvio
AU - Veronica, Corsetti
AU - Ciasca, Gabriele
AU - Ciotti, Maria Teresa
AU - Pittaluga, Anna
AU - Olivero, Gunedalina
AU - Feligioni, Marco
AU - Iannuzzi, Filomena
AU - Latina, Valentina
AU - Maria Sciacca, Michele Francesco
AU - Sinopoli, Alessandro
AU - Milardi, Danilo
AU - Pappalardo, Giuseppe
AU - De Spirito, Marco
AU - Papi, Massimiliano
AU - Atlante, Anna
AU - Bobba, Antonella
AU - Borreca, Antonella
AU - Calissano, Pietro
AU - Amadoro, Giuseppina
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Alzheimer
KW - tau
KW - Alzheimer
KW - tau
UR - http://hdl.handle.net/10807/101369
U2 - 10.18632/oncotarget.17371
DO - 10.18632/oncotarget.17371
M3 - Article
SN - 1949-2553
VL - 8
SP - 64745
EP - 64778
JO - Oncotarget
JF - Oncotarget
ER -