Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model.
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Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model. / Sydow, Astrid; Ann, Van der Jeugd; Zheng, Fang; Ahmed, Tariq; Balschun, Detlef; Petrova, Olga; Drexler, Dagmar; Zhou, Lepu; Rune, Gabriele M.; Mandelkow, Eckhard; D'Hooge, Rudi; Alzheimer, Christian; Mandelkow, Eva-Maria.
In: J MOL NEUROSCI, Vol. 45, No. 3, 3, 2011, p. 432-437.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model.
AU - Sydow, Astrid
AU - Ann, Van der Jeugd
AU - Zheng, Fang
AU - Ahmed, Tariq
AU - Balschun, Detlef
AU - Petrova, Olga
AU - Drexler, Dagmar
AU - Zhou, Lepu
AU - Rune, Gabriele M.
AU - Mandelkow, Eckhard
AU - D'Hooge, Rudi
AU - Alzheimer, Christian
AU - Mandelkow, Eva-Maria
PY - 2011
Y1 - 2011
N2 - 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 ?K280 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.
AB - 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 ?K280 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.
KW - Animals
KW - Humans
KW - Mice
KW - Mutation
KW - Memory/physiology
KW - Cognition Disorders/pathology/physiopathology
KW - Disease Models, Animal
KW - Learning/physiology
KW - Long-Term Potentiation/physiology
KW - Mice, Transgenic
KW - Tauopathies/genetics/pathology/physiopathology
KW - tau Proteins/chemistry/genetics/metabolism
KW - Animals
KW - Humans
KW - Mice
KW - Mutation
KW - Memory/physiology
KW - Cognition Disorders/pathology/physiopathology
KW - Disease Models, Animal
KW - Learning/physiology
KW - Long-Term Potentiation/physiology
KW - Mice, Transgenic
KW - Tauopathies/genetics/pathology/physiopathology
KW - tau Proteins/chemistry/genetics/metabolism
M3 - SCORING: Journal article
VL - 45
SP - 432
EP - 437
JO - J MOL NEUROSCI
JF - J MOL NEUROSCI
SN - 0895-8696
IS - 3
M1 - 3
ER -
