TY  - JOUR
AU  - Decker, Jochen Martin
AU  - Krüger, Lars
AU  - Sydow, Astrid
AU  - Zhao, Shanting
AU  - Frotscher, Michael
AU  - Mandelkow, Eckhard
AU  - Mandelkow, Eva-Maria
TI  - Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation.
JO  - Acta Neuropathologica Communications
VL  - 3
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DZNE-2020-04404
SP  - 23
PY  - 2015
AB  - We used an inducible mouse model expressing the Tau repeat domain with the pro-aggregant mutation ΔK280 to analyze presynaptic Tau pathology in the hippocampus.Expression of pro-aggregant Tau(RDΔ) leads to phosphorylation, aggregation and missorting of Tau in area CA3. To test presynaptic pathophysiology we used electrophysiology in the mossy fiber tract. Synaptic transmission was severely disturbed in pro-aggregant Tau(RDΔ) and Tau-knockout mice. Long-term depression of the mossy fiber tract failed in pro-aggregant Tau(RDΔ) mice. We observed an increase in bouton size, but a decline in numbers and presynaptic markers. Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation. Calcium imaging revealed progressive calcium dysregulation in boutons of pro-aggregant Tau(RDΔ) mice. In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation. Ultrastructural analysis revealed a severe depletion of synaptic vesicles pool in accordance with synaptic transmission impairments.We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.
KW  - Animals
KW  - Calcium: physiology
KW  - Calcium Signaling: physiology
KW  - Cell Culture Techniques
KW  - Disease Models, Animal
KW  - Electrophysiology
KW  - Hippocampus: physiology
KW  - Long-Term Potentiation: physiology
KW  - Mice
KW  - Mice, Knockout
KW  - Mossy Fibers, Hippocampal: physiology
KW  - Neuronal Plasticity: physiology
KW  - Synaptic Transmission: physiology
KW  - tau Proteins: deficiency
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - tau Proteins (NLM Chemicals)
KW  - Calcium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25853683
C2  - pmc:PMC4384391
DO  - DOI:10.1186/s40478-015-0193-3
UR  - https://pub.dzne.de/record/138082
ER  -