Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

Oakley, Holly D.; Cole, Sarah L.; Logan, Sreemathi; Maus, Erika; Shao, Peng; Craft, Jeffery; Guillozet-Bongaarts, Angela L.; Ohno, Minoru; Disterhoft, John F.; Eldik, Linda Van; Berry, Robert W.; Vassar, Robert

doi:10.1523/jneurosci.1202-06.2006

Cited by 2,886 publications

(4,162 citation statements)

References 61 publications

Supporting

275

Mentioning

3,827

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have demonstrated that long‐term RF‐EMF exposure may have beneficial effects on cognitive deficits of AD transgenic mice [Arendash et al, 2010; Jeong et al, 2015], and this effect might be related to reduced Aβ deposition. Therefore, we used the 5xFAD transgenic mouse model, which shows AD‐like pathology, such as early Aβ plaque formation in brain parenchyma and behavioral deficits [Oakley et al, 2006]. We exposed 5xFAD mice to RF‐EMF for 3 months to evaluate the effect of RF‐EMF on memory impairment and Aβ pathology.…”

Section: Discussionmentioning

confidence: 99%

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice

Son

Jeong

Kwon³

et al. 2016

Bioelectromagnetics

View full text Add to dashboard Cite

The increased use of mobile phones has generated public concern about the impact of radiofrequency electromagnetic fields (RF‐EMF) on health. In the present study, we investigated whether RF‐EMFs induce molecular changes in amyloid precursor protein (APP) processing and amyloid beta (Aβ)‐related memory impairment in the 5xFAD mouse, which is a widely used amyloid animal model. The 5xFAD mice at the age of 1.5 months were assigned to two groups (RF‐EMF‐ and sham‐exposed groups, eight mice per group). The RF‐EMF group was placed in a reverberation chamber and exposed to 1950 MHz electromagnetic fields for 3 months (SAR 5 W/kg, 2 h/day, 5 days/week). The Y‐maze, Morris water maze, and novel object recognition memory test were used to evaluate spatial and non‐spatial memory following 3‐month RF‐EMF exposure. Furthermore, Aβ deposition and APP and carboxyl‐terminal fragment β (CTFβ) levels were evaluated in the hippocampus and cortex of 5xFAD mice, and plasma levels of Aβ peptides were also investigated. In behavioral tests, mice that were exposed to RF‐EMF for 3 months did not exhibit differences in spatial and non‐spatial memory compared to the sham‐exposed group, and no apparent change was evident in locomotor activity. Consistent with behavioral data, RF‐EMF did not alter APP and CTFβ levels or Aβ deposition in the brains of the 5xFAD mice. These findings indicate that 3‐month RF‐EMF exposure did not affect Aβ‐related memory impairment or Aβ accumulation in the 5xFAD Alzheimer's disease model. Bioelectromagnetics. 37:391–399, 2016. © 2016 The Authors Bioelectromagnetics published by Wiley Periodicals, Inc. on behalf of Bioelectromagnetics Society.

show abstract

Section: Discussionmentioning

confidence: 99%

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice

Son

Jeong

Kwon³

et al. 2016

Bioelectromagnetics

View full text Add to dashboard Cite

show abstract

“…Interestingly, transgenic mice overexpressing hAPP without AD‐related mutations, like I5, barely develop any Aβ deposits at high age (Mucke et al ., 2000). However, mice overexpressing mutant hAPP Swedish display Aβ deposits starting at around 10 months of age, for example Tg2576 (Hsiao et al ., 1996), while mice overexpressing mutant hAPP Swedish in combination with mutant γ ‐secretase components generate Aβ deposits even faster, for example 5xFAD (Oakley et al ., 2006). …”

Section: Introductionmentioning

confidence: 99%

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

View full text Add to dashboard Cite

SummaryAlzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age‐related and brain region‐specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP‐transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP‐transgenic mouse and one APP‐transgenic rat model. We observed remarkable differences in expression levels and brain region‐specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP‐transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals.

show abstract

“…Here, we assessed SUMO1 conjugation during alterations of proteostasis, as observed during aging and the development of AD‐like pathology. For this purpose, we crossed the His 6 ‐HA‐SUMO1 knock‐in (KI) with the 5XFAD mouse model that rapidly recapitulates major features of AD, including neuronal loss in hippocampal and cortical regions, and age‐dependent synapse loss (Oakley et al., 2006). We generated double mutant mice that are referred to here as KI/AD; non‐KI and non‐AD mice were used as controls, and are referred to as KI/WT, WT/AD, and WT/WT.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, we used the 5XFAD mouse model that shows clear age‐related AD features such as amyloid deposition, synaptic loss, and age‐related cognitive decline (Oakley et al., 2006). Strikingly, we found age‐related alterations of SUMO1 conjugation in this AD model but did not detect any significant changes in SUMO1 conjugation related to an increased amyloid burden.…”

Section: Introductionmentioning

confidence: 99%

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

et al. 2018

View full text Add to dashboard Cite

SummaryA proper equilibrium of post‐translational protein modifications is essential for normal cell physiology, and alteration in these processes is key in neurodegenerative disorders such as Alzheimer's disease. Recently, for instance, alteration in protein SUMOylation has been linked to amyloid pathology. In this work, we aimed to elucidate the role of protein SUMOylation during aging and increased amyloid burden in vivo using a His6‐HA‐SUMO1 knock‐in mouse in the 5XFAD model of Alzheimer's disease. Interestingly, we did not observe any alteration in the levels of SUMO1‐conjugation related to Alzheimer's disease. SUMO1 conjugates remained localized to neuronal nuclei upon increased amyloid burden and during aging and were not detected in amyloid plaques. Surprisingly however, we observed age‐related alterations in global levels of SUMO1 conjugation and at the level of individual substrates using quantitative proteomic analysis. The identified SUMO1 candidate substrates are dominantly nuclear proteins, mainly involved in RNA processing. Our findings open novel directions of research for studying a functional link between SUMOylation and its role in guarding nuclear functions during aging.

show abstract

Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

Cited by 2,886 publications

References 61 publications

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice

1950 MHz radiofrequency electromagnetic fields do not aggravate memory deficits in 5xFAD mice

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

Contact Info

Product

Resources

About