title: Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration.
abstract: A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland, UK.
authors.forename: V
authors.initials: V
authors.lastname: Melis
authors.forename: C
authors.initials: C
authors.lastname: Zabke
authors.forename: K
authors.initials: K
authors.lastname: Stamer
authors.forename: M
authors.initials: M
authors.lastname: Magbagbeolu
authors.forename: K
authors.initials: K
authors.lastname: Schwab
authors.forename: P
authors.initials: P
authors.lastname: Marschall
authors.forename: R W
authors.initials: RW
authors.lastname: Veh
authors.forename: S
authors.initials: S
authors.lastname: Bachmann
authors.forename: S
authors.initials: S
authors.lastname: Deiana
authors.forename: P-H
authors.initials: PH
authors.lastname: Moreau
authors.forename: K
authors.initials: K
authors.lastname: Davidson
authors.forename: K A
authors.initials: KA
authors.lastname: Harrington
authors.forename: J E
authors.initials: JE
authors.lastname: Rickard
authors.forename: D
authors.initials: D
authors.lastname: Horsley
authors.forename: R
authors.initials: R
authors.lastname: Garman
authors.forename: M
authors.initials: M
authors.lastname: Mazurkiewicz
authors.forename: G
authors.initials: G
authors.lastname: Niewiadomska
authors.forename: C M
authors.initials: CM
authors.lastname: Wischik
authors.forename: C R
authors.initials: CR
authors.lastname: Harrington
authors.forename: G
authors.initials: G
authors.lastname: Riedel
authors.forename: F
authors.initials: F
authors.lastname: Theuring
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000473:pathology*; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins