Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)
By M. Ramsden, L. Kotilinek, C. Forster, Jennifer B. Paulson, E. McGowan, K. Santacruz, A. Guimaraes, Mei Yue, Jada Lewis, G. Carlson and 2 more. Journal of Neuroscience, 2005
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Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tauP301L)4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca2+ calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tauP301L)4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation- and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tauP301L expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tauP301L)4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.
Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology
View Paper: https://www.semanticscholar.org/paper/8b78a031ada77cdaa995a8d897ad8858f7602a4d
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Citations in the corpus
- Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration (2010, methodology): “5 months of age, prior to the loss of synapses or neurons (Ramsden et al., 2005; Santacruz et al., 2005) and found spatial memory deficits first appearing in the older mice (Figure 1).”
- The Basal Forebrain Cholinergic Projection System in Mice Neuron Types in the Basal Forebrain - Chapter 28 The Mouse Nervous System (2012, background): “Islet1, a LIM homeodomain transcription factor, is richly expressed deep in the MGE, LGE and in the primordial septum at E15 in rat and in the developing striatum at E18–20.”
- Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning (2015, neutral): “neurodegeneration with associated age-dependent cognitivebehavioral deficits (Ramsden et al., 2005).”