Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy: a light and electron microscopy study

Ludvigson, Adam E.; Luebke, Jennifer I.; Lewis, Jada; Peters, Alan

doi:10.1007/s00429-010-0295-4

Cited by 21 publications

(26 citation statements)

References 38 publications

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“…Using Hoescht labeling, we confirmed that neuronal nuclei appear healthy and intact the day after a new tangle forms (de Calignon et al 2010). Postmortem, we have found that rTg4510 mice do not develop “ghost” tangles, which has been confirmed with electron microscopy in this model (Ludvigson et al 2010), so the NFT that we follow for several days in vivo are highly likelytobeliveneurons.…”

Section: In Vivo Imaging Directly Addresses Whether Tangles Cause Celsupporting

confidence: 75%

Are Tangles as Toxic as They Look?

et al. 2011

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Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated and misfolded tau protein characteristic of Alzheimer's disease and other tauopathies. Classic cross-sectional studies of Alzheimer patient brains showed associations of tangle accumulation with neuronal loss, synapse loss, and dementia, which led to the supposition that tangles are toxic to neurons. More recent advances in imaging techniques and mouse models have allowed the direct exploration of the question of toxicity of aggregated versus soluble tau and have surprisingly challenged the view of tangles as toxic species in the brain. Here, we review these recent experiments on the nature of the toxicity of tau with particular emphasis on our experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangle-bearing neurons. Neurofibrillary tangles (NFT) were first described in 1906 by Alois Alzheimer based on Bielschowsky silver staining of the brain of his demented patient Auguste D (Alzheimer 1907; Goedert and Spillantini 2006). These intraneuronal aggregates have subsequently been found to be composed primarily of hyperphosphorylated tau protein and are definitive pathological lesions not only in Alzheimer's disease but also in a class of neurodegenerative tauopathies (Goedert et al. 1988; Spires-Jones et al. 2009). NFT pathology in Alzheimer's disease (AD) correlates closely with cognitive decline and synapse and neuronal loss (Braak and Braak 1997; Bretteville and Planel 2008; Congdon and Duff 2008; Mocanu et al. 2008b; Spires-Jones et al. 2009). As a result, NFT have long been considered indicative of impending neuronal cell death. More recent evidence, however, opposes this classical view. Here we review evidence addressing the question of whether NFT cause structural or functional neuronal damage.

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Section: In Vivo Imaging Directly Addresses Whether Tangles Cause Celsupporting

confidence: 75%

Are Tangles as Toxic as They Look?

et al. 2011

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“…In addition, volumetric MRI studies of both the hippocampus and cortical thickness in rTg4510 mice have indicated the onset of neurodegeneration at around 5 months (Ludvigson et al, 2011). Thus, we began measuring axonal transport rates at 5 and 10 months of age in rTg4510 mice and their littermates.…”

Section: Resultsmentioning

confidence: 99%

In vivo axonal transport deficits in a mouse model of fronto-temporal dementia

Majid

Ali

Venkitaramani

et al. 2014

NeuroImage: Clinical

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BackgroundAxonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium–calmodulin kinase II promoter. This mouse model exhibits tau pathology, neurodegeneration in the forebrain, and associated behavioral deficits beginning at 4–5 months of age.Animal modelrTg4510 transgenic mice were used in these studies. Mice were given 2 μL of MnCl2 in each nostril 1 h prior to Magnetic Resonance Imaging (MRI). Following MnCl2 nasal lavage, mice were imaged using Manganese enhanced Magnetic Resonance Imaging (MEMRI) Protocol with TE = 8.5 ms, TR = 504 ms, FOV = 3.0 cm, matrix size = 128 × 128 × 128, number of cycles = 15 with each cycle taking approximately 2 min, 9 s, and 24 ms using Paravision software (BrukerBioSpin, Billerica, MA). During imaging, body temperature was maintained at 37.0 °C using an animal heating system (SA Instruments, Stony Brook, NY).Data analysisResulting images were analyzed using Paravision software. Regions of interest (ROI) within the olfactory neuronal layer (ONL) and the water phantom consisting of one pixel (ONL) and 9 pixels (water) were selected and copied across each of the 15 cycles. Signal intensities (SI) of ONL and water phantom ROIs were measured. SI values obtained for ONL were then normalized the water phantom SI values. The correlation between normalized signal intensity in the ONL and time were assessed using Prism (GraphPad Software, San Diego, CA).ResultsUsing the MEMRI technique on 1.5, 3, 5, and 10-month old rTg4510 mice and littermate controls, we found significant axonal transport deficits present in the rTg4510 mice beginning at 3 months of age in an age-dependent manner. Using linear regression analysis, we measured rates of axonal transport at 1.5, 3, 5, and 10 months of age in rTg4510 and WT mice. Axonal transport rates were observed in rTg4510 mice at 48% of WT levels at 3 months, 40% of WT levels at 5 months, and 30% of WT levels at 10 months of age. In order to determine the point at which tau appears in the cortex, we probed for phosphorylated tau levels, and found that pSer262 is present at 3 months of age, not earlier at 1.5 months of age, but observed no pathological tau species until 6 months of age, months after the onset of the transport deficits. In addition, we saw localization of tau in the ONL at 6 months of age.DiscussionIn our study, we identified the presence of age-dependent axonal transport deficits beginning at 3 months of age in rTg4510 mice. We correlated these deficits at 3 months to the presence of hyperphosphorylated tau in the brain and the presence within the olfactory epithelium. We observed tau pathology not...

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“…The classic histopathological marker of tauopathy are neurofibrillary tangles (NFTs). Aggregated tau can be found in diseased dendrites, axons, and NFTs in the soma (Ludvigson et al., 2011). However, evidence suggests that aggregated tau may not be a crucial factor in synaptic or structural abnormalities, even quite late in tauopathy (Rocher et al., 2010).…”

Section: Discussionmentioning

confidence: 99%

Altered Synapse Stability in the Early Stages of Tauopathy

Jackson¹,

Witton

Johnson

et al. 2017

Cell Reports

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SummarySynapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease.

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Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy: a light and electron microscopy study

Cited by 21 publications

References 38 publications

Are Tangles as Toxic as They Look?

Are Tangles as Toxic as They Look?

In vivo axonal transport deficits in a mouse model of fronto-temporal dementia

Altered Synapse Stability in the Early Stages of Tauopathy

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