The 5XFAD Mouse Model of Alzheimer’s Disease Exhibits an Age-Dependent Increase in Anti-Ceramide IgG and Exogenous Administration of Ceramide Further Increases Anti-Ceramide Titers and Amyloid Plaque Burden

Dinkins, Michael B.; Dasgupta, Somsankar; Wang, Guanghu; Zhu, Gu; He, Qian; Kong, Ji Na; Bieberich, Erhard

doi:10.3233/jad-150088

Cited by 66 publications

(57 citation statements)

References 36 publications

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“…The ThioS-positive plaque burden in 14-week female 5XFAD was found to be ~0.7% (calculated from the data in [43]) and the burden of plaques stained with X-34, another stain for fibrillar Aβ, in 4-month mice (gender unspecified) was ~0.8% [9], close to the 0.5% ThioS burden that we found in 3-month female 5XFAD mice. In 6-month 5XFAD mice (both males and females used in this study), the ThioS burden has been reported as 2.5–3% [44], similar to the 3.6% that we found in 6–9-month female mice.…”

Section: Discussionsupporting

confidence: 71%

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Liu

Reichl

Rao

et al. 2017

JAD

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There exist several dozen lines of transgenic mice that express human amyloid-β precursor protein (AβPP) with Alzheimer’s disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ~4.5 times that of 21-month Tg2576 mice and ~15 times that of 21–24-month rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

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Section: Discussionsupporting

confidence: 71%

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Liu

Reichl

Rao

et al. 2017

JAD

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“…However, females with AD generally have more neuropathology and cognitive impairment than males, and neuropathology has a stronger relationship with symptomology and disease diagnosis in females than males . In 5xFAD mice, females also show more AD‐related pathology than males, including increased Aβ‐plaque load, and elevated levels of APP and Aβ‐42 as early as 4‐6 months of age (Sadleir et al, 2015) . These sex differences cannot simply be attributed to differences in transgene expression, given similar levels of hAPP and hPS1 mRNA have been observed in male and female 5xFAD mice …”

Section: Discussionmentioning

confidence: 99%

“…48 In 5xFAD mice, females also show more ADrelated pathology than males, including increased Aβ-plaque load, 33,34 and elevated levels of APP and Aβ-42 as early as 4-6 months of age (Sadleir et al, 2015). 31 These sex differences cannot simply be attributed to differences in transgene expression, given similar levels of hAPP and hPS1 mRNA have been observed in male and female 5xFAD mice. 49 Previous studies documenting motor dysfunction in 5xFAD mice have used only one sex of 5xFAD mice, 22,24 and this is the first study to examine sex differences in motor impairments.…”

Section: Are There Sex Differences In the Progression Of The Motor mentioning

confidence: 99%

“…Sex differences have been shown in the lifespan 27 and in the severity of diseaserelated phenotypes in AD mouse models. [28][29][30] In 5xFAD mice, females show higher levels of APP and Aβ-42 than males 20,31,32 , and also show increased plaque load. 33,34 The majority of studies assessing motor function in 5xFAD mice use female mice, 22,24,25 and therefore, it is not yet clear how the progression of motor impairments may differ in males.…”

Section: Introductionmentioning

confidence: 99%

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Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

O’Leary

Mantolino

Stover

et al. 2018

Genes Brain and Behavior

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Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf im on motor function, suggesting that Dysf im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.

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“…Neuroblastoma-derived exosomes injected into an AD-model mouse brain were shown to take up Aβ and reduce Aβ levels, amyloid depositions, as well as Aβ-mediated synaptotoxicity in the hippocampus (Yuyama et al 2014, Yuyama et al 2015). In contrast, an increase in serum exosome levels correlated with an enhanced amyloid plaques in the brains of the 5XFAD mouse model of AD (Dinkins et al 2015). In additon, reducing exosome secretion by the nSMase2 inhibitor GW4869 resulted in a diminished amount of amyloid plaques in the same mouse model (Dinkins et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology

András

Léda

Garcia‐Contreras

et al. 2017

Molecular and Cellular Neuroscience

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HIV-infected brains are characterized by increased amyloid beta (Aβ) deposition. It is believed that the blood-brain barrier (BBB) is critical for Aβ homeostasis and contributes to Aβ accumulation in the brain. Extracellular vesicles (ECV), like exosomes, recently gained a lot of attention as potentially playing a significant role in Aβ pathology. In addition, HIV-1 hijacks the exosomal pathway for budding and release. Therefore, we investigated the involvement of BBB-derived ECV in the HIV-1-induced Aβ pathology in the brain. Our results indicate that HIV-1 increases ECV release from brain endothelial cells as well as elevates their Aβ cargo when compared to controls. Interestingly, brain endothelial cell-derived ECV transferred Aβ to astrocytes and pericytes. Infusion of brain endothelial ECV carrying fluorescent Aβ into the internal carotid artery of mice resulted in Aβ fluorescence associated with brain microvessels and in the brain parenchyma. These results suggest that ECV carrying Aβ can be successfully transferred across the BBB into the brain. Based on these observations, we conclude that HIV-1 facilitates the shedding of brain endothelial ECV carrying Aβ; a process that may increase Aβ exposure of cells of neurovascular unit, and contribute to amyloid deposition in HIV-infected brain.

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The 5XFAD Mouse Model of Alzheimer’s Disease Exhibits an Age-Dependent Increase in Anti-Ceramide IgG and Exogenous Administration of Ceramide Further Increases Anti-Ceramide Titers and Amyloid Plaque Burden

Cited by 66 publications

References 36 publications

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology

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