Title: Reversibility of Tau-Related Cognitive Defects in a Regulatable FTD Mouse Model
Authors: Sydow, Astrid ×
Van der Jeugd, Anneke
Zheng, Fang
Ahmed, Tariq
Balschun, Detlef
Petrova, Olga
Drexler, Dagmar
Zhou, Lepu
Rune, Gabriele
Mandelkow, Eckhard
D'Hooge, Rudi
Alzheimer, Christian
Mandelkow, Eva-Maria #
Issue Date: Nov-2011
Publisher: Birkhäuser Boston
Series Title: Journal of Molecular Neuroscience vol:45 issue:3 pages:432-437
Abstract: The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation ΔK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tau to aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates.
ISSN: 0895-8696
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Biological Psychology
× corresponding author
# (joint) last author

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