Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice

Kastyak-Ibrahim, Marzena Z.; Curzio, Domenico L. Di; Buist, Richard; Herrera, Sheryl L.; Albensi, Benedict C.; Bigio, Marc R. Del; Martin, Melanie

doi:10.1016/j.mri.2013.06.013

Cited by 23 publications

(31 citation statements)

References 35 publications

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“…The lack of detectable differences in DTI metrics in the cortex, in which several tau-positive neurons were evident, coupled with the altered metrics found in the hippocampus, which demonstrated both plaques and tangles, suggests for a primary contribution of the plaque deposition to the DTI signal reported here, or possibly the combination of the two pathological features. Consistent with this interpretation is the finding of a the lack of DTI differences in the slice containing the entorhinal cortex, in which immunoreactivity for pathological tau was particularly intense in the subiculum, as previously reported [29,44,45]. Using diffusion weighted imaging, however, TgCRND8 mice failed to show altered diffusivity in gray matter regions, including the hippocampus and cerebral cortex [24], regions with robust plaque deposition in the absence of neurofibrillary tangles, suggesting it is the co-occurrence of both A␤ plaques and neurofibrillary tangles that contributes to the altered DTI measures in the present study.…”

Section: Discussionsupporting

confidence: 86%

“…The triple transgenic (3xTg) AD mouse exhibits several age-dependent hallmarks of the disorder, including the presence of both brain A␤ plaques and neurofibrillary tangles as well as memory deficits [28]. Assessment of white matter in 3xTg mice using DTI revealed no significant differences between age-matched controls [29]. Whether microstructural abnormalities in gray matter in this common AD model can be detected using DTI, however, has not been determined.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer’s Disease with Diffusion Tensor Imaging

Snow

Dale

O’Brien-Moran

et al. 2017

JAD

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Abstract.A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-␤ (A␤) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both A␤ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p < 0.01) and axial diffusivity (p < 0.05) were detected only in the hippocampus, in which both congophilic A␤ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer’s Disease with Diffusion Tensor Imaging

Snow

Dale

O’Brien-Moran

et al. 2017

JAD

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“…This is due to previous measurements on mouse models of AD which showed no significant changes in white matter (14).…”

Section: Alzheimer's Disease Data Setmentioning

confidence: 77%

“…The mouse models used in these studies were single transgenic models (see Methods section) which have not been observed to have white matter differences (14). Because of high school science fair rules, images from mouse models of AD with white matter changes could not be used (15).…”

Section: Alzheimer's Disease Data Setmentioning

confidence: 99%

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Comparison of Tractography in Mouse Models of Multiple Sclerosis and Alzheimer’s Disease

BeltranoWinnica

O’Brien-MoranZoe

HerreraSheryl

et al. 2017

STEM Fellowship Journal

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Tractography is a method that finds fiber tracts within a sample (e.g. a mouse brain), which allows users to better understand how different regions and structures of the brain are connected. The only animal magnetic resonance imaging (MRI) centre in Manitoba does not have the software to perform tractography on their images. This severely limits the variation of studies that can be performed in the centre. The goal of this project was to develop a robust tractography analysis method for the centre. The designed tractography analysis method was tested on known phantoms (objects which are meant to mimic tissue) such as celery, and then on animal brain samples from various mouse models of multiple sclerosis and Alzheimer's disease. The first test of the tractography analysis method was to determine if the tracts within the corpus collosum in the brain of mice differ between mouse models. Tracts in the corpus callosum were measured using the developed tractography analysis method.Single factor ANOVA found no differences between the tractography parameters in tracts of the corpora callosa in a mouse model of multiple sclerosis (MS) and the corresponding wildtype mouse, nor between a mouse model of Alzheimer's disease (AD) and its corresponding wildtype mouse. The tractography analysis method was successfully developed and is now ready for use in more complex models.

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Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

et al. 2020

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Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein.In recent years, Aβ-immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single-chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv-h3D6 generated by our research group derives from this monoclonal antibody, which targets the N-terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils.In this study, 3xTg-AD mice were intraperitoneally and monthly treated with 100 μg of scFv-h3D6 (a dose of~3.3 mg/kg) or PBS, from 5 to 12 months of age (−mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non-invasive manner and allowing to monitor its development across time.Compared with the genetic background, 3xTg-AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ 1-42 at 12-mo, and an inflammation process at this age, in both the hippocampus (IL-6 and mIns) and cortex (IL-6). In addition, treatment with scFv-h3D6 partially recovered the values in brain volume, and Aβ, IL-6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.Abbreviations: 3xTg-AD, triple-transgenic mouse model of AD.; 6E10+, mAb-6E10 immunoreactive

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Neurofibrillary tangles and plaques are not accompanied by white matter pathology in aged triple transgenic-Alzheimer disease mice

Cited by 23 publications

References 35 publications

In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer’s Disease with Diffusion Tensor Imaging

In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer’s Disease with Diffusion Tensor Imaging

Comparison of Tractography in Mouse Models of Multiple Sclerosis and Alzheimer’s Disease

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

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