Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration

V Melis, C Zabke, K Stamer, M Magbagbeolu, K Schwab, P. Marshall, R. W. Weh, S Bachmann, S Deiana, P H Moreau, K Davidson, K A Harrington, J E Rickard, D Horsley, R Garman, M Mazurkiewicz, G Niewiadomska, C M Wischik, C R Harrington, G Riedel & 1 others F. Theuring

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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.
Original languageEnglish
Pages (from-to)2199-2222
Number of pages24
JournalCellular and Molecular Life Sciences
Volume72
Issue number11
Early online date19 Dec 2014
DOIs
Publication statusPublished - Jun 2015

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Frontotemporal Lobar Degeneration
Tauopathies
Alzheimer Disease
Phenotype
Pathology
Entorhinal Cortex
Episodic Memory
Memory Disorders
Protein Sorting Signals
Endoplasmic Reticulum
Psychiatry
Rodentia
Hippocampus
Phosphorylation
Learning
Neurons
Mutation
Membranes
Brain

Keywords

  • Tau protein
  • transgenic mice
  • P301L
  • truncated cDNA Tau296-390
  • motor impairment
  • spatial cognition

Cite this

Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration. / Melis, V; Zabke, C; Stamer, K; Magbagbeolu, M; Schwab, K; Marshall, P.; Weh, R. W.; Bachmann, S; Deiana, S; Moreau, P H; Davidson, K; Harrington, K A; Rickard, J E; Horsley, D; Garman, R; Mazurkiewicz, M; Niewiadomska, G; Wischik, C M; Harrington, C R; Riedel, G; Theuring, F.

In: Cellular and Molecular Life Sciences, Vol. 72, No. 11, 06.2015, p. 2199-2222.

Research output: Contribution to journalArticle

Melis, V, Zabke, C, Stamer, K, Magbagbeolu, M, Schwab, K, Marshall, P, Weh, RW, Bachmann, S, Deiana, S, Moreau, PH, Davidson, K, Harrington, KA, Rickard, JE, Horsley, D, Garman, R, Mazurkiewicz, M, Niewiadomska, G, Wischik, CM, Harrington, CR, Riedel, G & Theuring, F 2015, 'Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration', Cellular and Molecular Life Sciences, vol. 72, no. 11, pp. 2199-2222. https://doi.org/10.1007/s00018-014-1804-z
Melis, V ; Zabke, C ; Stamer, K ; Magbagbeolu, M ; Schwab, K ; Marshall, P. ; Weh, R. W. ; Bachmann, S ; Deiana, S ; Moreau, P H ; Davidson, K ; Harrington, K A ; Rickard, J E ; Horsley, D ; Garman, R ; Mazurkiewicz, M ; Niewiadomska, G ; Wischik, C M ; Harrington, C R ; Riedel, G ; Theuring, F. / Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration. In: Cellular and Molecular Life Sciences. 2015 ; Vol. 72, No. 11. pp. 2199-2222.
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T1 - Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration

AU - Melis, V

AU - Zabke, C

AU - Stamer, K

AU - Magbagbeolu, M

AU - Schwab, K

AU - Marshall, P.

AU - Weh, R. W.

AU - Bachmann, S

AU - Deiana, S

AU - Moreau, P H

AU - Davidson, K

AU - Harrington, K A

AU - Rickard, J E

AU - Horsley, D

AU - Garman, R

AU - Mazurkiewicz, M

AU - Niewiadomska, G

AU - Wischik, C M

AU - Harrington, C R

AU - Riedel, G

AU - Theuring, F.

N1 - Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. Acknowledgments From the Berlin Laboratory, we thank Ingo Voigt for performing the injections of the two constructs into the oocytes, Bettina Seelhorst for her extensive technical assistance, Anna Thoma for taking specific care of the animals, and John Horn, Charite Core Facility for electron microscopy for performing expert analyses in ultra-cryosections with immunogold technique. Expert comments on the manuscript from Silke Frahm-Barske (Berlin) are also acknowledged. Special thanks to Bob Switzer at NeuroScience Associates Inc. for embedding, sectioning and staining mouse brains. This work was funded by TauRx Therapeutics, Singapore. C.R.H. and C.M.W. declare that they are officers in TauRx Therapeutics Ltd.

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N2 - 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.

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KW - Tau protein

KW - transgenic mice

KW - P301L

KW - truncated cDNA Tau296-390

KW - motor impairment

KW - spatial cognition

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DO - 10.1007/s00018-014-1804-z

M3 - Article

VL - 72

SP - 2199

EP - 2222

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

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