title: Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model.
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.
authors.affiliation: Max Planck Unit for Structural Molecular Biology, c/o DESY, 22607, Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Sydow
authors.forename: Ann
authors.initials: A
authors.lastname: Van der Jeugd
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmed
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
authors.forename: Olga
authors.initials: O
authors.lastname: Petrova
authors.forename: Dagmar
authors.initials: D
authors.lastname: Drexler
authors.forename: Lepu
authors.initials: L
authors.lastname: Zhou
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rune
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D024801:Tauopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins