Mutations: MAPT P301L
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: Thy1-hTau.P301L
Genetic Background: FVB/N
Availability: Available at the CRO reMYND
Tau hyperphosphorylation and conformational changes in the brain parenchyma start around seven months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex (Terwel et al., 2005). Age-dependent increase in total tau measured in the cerebral spinal fluid (personal communication, reMYND).
Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014). However, at young ages (eight to ten weeks), Tau P301L mice actually outperform wild-type littermates in object recognition memory (Boekhoorn et al., 2006). The mice also develop progressive motor impairment and inactivity, accompanied by increased clasping of hind and then forelimbs around seven months (Terwel et al., 2005).
Premature death, attributed to hindbrain tauopathy, generally occurs between eight and 12 months (Dutschmann et al., 2010). Premature death is preceded by weight loss, hyperkyphosis, reduced activity, and upper airway dysfunction. At a young age (eight to ten weeks), Tau P301L mice have enhanced long-term potentiation in the dentate gyrus. This is before hyperphosphorylation and tauopathy are apparent (Boekhoorn et al., 2006), and may be due to acclerated dendritic spine maturation (Kremer et al., 2011).
These transgenic mice overexpress human tau, specifically the 4R/2N isoform, bearing the P301L mutation under the control of the neuron-specific murine Thy1 promoter (Terwel et al., 2005).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
Hyperphosphorylation, conformational changes, and aggregation of tau resulting in tangle-like pathology by 8 months.
Astrogliosis by 7 months.
Unknown at advanced age. Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).
Changes in LTP/LTD
Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).
Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).
- Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem. 2005 Feb 4;280(5):3963-73. PubMed.
- Maurin H, Chong SA, Kraev I, Davies H, Kremer A, Seymour CM, Lechat B, Jaworski T, Borghgraef P, Devijver H, Callewaert G, Stewart MG, Van Leuven F. Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopathy. PLoS One. 2014;9(2):e87605. Epub 2014 Feb 3 PubMed.
- Boekhoorn K, Terwel D, Biemans B, Borghgraef P, Wiegert O, Ramakers GJ, de Vos K, Krugers H, Tomiyama T, Mori H, Joels M, Van Leuven F, Lucassen PJ. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006 Mar 29;26(13):3514-23. PubMed.
- Dutschmann M, Menuet C, Stettner GM, Gestreau C, Borghgraef P, Devijver H, Gielis L, Hilaire G, Van Leuven F. Upper airway dysfunction of Tau-P301L mice correlates with tauopathy in midbrain and ponto-medullary brainstem nuclei. J Neurosci. 2010 Feb 3;30(5):1810-21. PubMed.
- Kremer A, Maurin H, Demedts D, Devijver H, Borghgraef P, Van Leuven F. Early improved and late defective cognition is reflected by dendritic spines in Tau.P301L mice. J Neurosci. 2011 Dec 7;31(49):18036-47. PubMed.
- Chong SA, Benilova I, Shaban H, De Strooper B, Devijver H, Moechars D, Eberle W, Bartic C, Van Leuven F, Callewaert G. Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer's disease: a multi-electrode array study. Neurobiol Dis. 2011 Dec;44(3):284-91. PubMed.