Cognitive and Sensorimotor Tasks for Assessing Functional Impairments in Mouse Models of Alzheimer’s Disease and Related Disorders

Boutajangout, Allal; Li, Yong Sheng; Quartermain, David; Sigurdsson, Einar M.

doi:10.1007/978-1-61779-551-0_35

Cited by 9 publications

(25 citation statements)

References 18 publications

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“…The mice went through adaptation and pre-tests using Rotarod, Open Field and Closed Field Symmetrical Tests on days 1–10 as we have detailed previously [30], followed by antibody injection on days 11 and 14 and retesting on days 15–18. Third injection was delivered on day 24 followed by fear-conditioning test on days 27–28, and perfusion on day 30.…”

Section: Methodsmentioning

confidence: 99%

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

Congdon

Yang

Rajamohamedsait

et al. 2016

Mol Neurodegeneration

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BackgroundA few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures.ResultsSurprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer’s paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6’s efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly.ConclusionsOverall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0126-z) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

Congdon

Yang

Rajamohamedsait

et al. 2016

Mol Neurodegeneration

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“…For the rotarod test, animals were placed onto a rod (diameter 3.6 cm) apparatus to assess differences in motor coordination and balance by measuring forelimb and hindlimb motor coordination and balance (Rotarod 7650 accelerating model; Ugo Basile, Varese, Italy) as we have previously described[ 35 ]. Each animal was tested for three sessions, with each session separated by 15 min, and measures were taken for rotarod speed when the animals fell from the top of the rotating barrel.…”

Section: Methodsmentioning

confidence: 99%

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

et al. 2015

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Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

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“…A video camera recorded the horizontal movements on the circular open field chamber (75 × 75 cm). Each animal were tested for 15 minutes, the total distance (cm), the mean resting time and the velocity (mean and maximum) were recorded, as previously published [13, 14]. …”

Section: Animal Behavior Assessmentsmentioning

confidence: 99%

“…The duration to explore the novel object is 6 minutes. The percentage short term memory score is calculated as previously published [13, 14]. …”

Section: Animal Behavior Assessmentsmentioning

confidence: 99%

“…Serial coronal brain sections (40 μm) were, placed in ethylene glycol cryo-protectant and stored at −20°C until they were used. Sections were immunolabeled with a monoclonal anti-Aβ antibody 6E10 as previously described [13, 14]. To detect the presence of the human stem cells in the mouse brains, the sections were immunolabeled with a mouse monoclonal antibody to human nuclear antigen (Cat.…”

Section: Animal Behavior Assessmentsmentioning

confidence: 99%

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Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer's Disease

Boutajangout¹,

Noorwali²,

Atta³

et al. 2016

CAR

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Introduction Alzheimer’s disease (AD) is the most common cause of dementia. The search for new treatments is made more urgent given its increasing prevalence resulting from the aging of the global population. Over the past 20 years, stem cell technologies have become an increasingly attractive option to both study and potentially treat neurodegenerative diseases. Several investigators reported a beneficial effect of different types of stem or progenitor cells on the pathology and cognitive function in AD models. Mouse models are one of the most important research tools for finding new treatment for AD. We aimed to explore the possible therapeutic potential of human umbilical cord mesenchymal stem cell xenografts in a transgenic (Tg) mouse model of AD. Methods APP/PS1 Tg AD model mice received human umbilical cord stem cells, directly injected into the carotid artery. To test the efficacy of the umbilical cord stem cells in this AD model, behavioral tasks (sensorimotor and cognitive tests) and immunohistochemical quantitation of the pathology was performed. Results Treatment of the APP/PS1 AD model mice, with human umbilical cord stem cells, produced a reduction of the amyloid beta burden in the cortex and the hippocampus which correlated with a reduction of the cognitive loss. Conclusion Human umbilical cord mesenchymal stem cells appear to reduce AD pathology in a transgenic mouse model as documented by a reduction of the amyloid plaque burden compared to controls. This amelioration of pathology correlates with improvements on cognitive and sensorimotor tasks.

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Cognitive and Sensorimotor Tasks for Assessing Functional Impairments in Mouse Models of Alzheimer’s Disease and Related Disorders

Cited by 9 publications

References 18 publications

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer's Disease

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