Longitudinal evaluation of Tau‐P301L transgenic mice reveals no cognitive impairments at 17 months of age

Kent, Brianne A.; Heath, Christopher; Kim, Chi Hun; Ahrens, Rosemary; Fraser, Paul E.; George-Hyslop, Peter St; Bussey, Timothy J.; Saksida, Lisa M.

doi:10.1002/brb3.896

Cited by 14 publications

(13 citation statements)

References 55 publications

(83 reference statements)

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“…This test was performed on half the mice. This novel object recognition test was modified and performed in a Y-maze based on previous protocols [ 40 – 42 ]. Novel object recognition data show that there are significant differences in preference index between groups ( p < 0.05; one-way ANOVA followed by Tukey’s multiple comparisons test).…”

Section: Resultsmentioning

confidence: 99%

“…The novel object recognition task is based on the natural tendency of mice to investigate a novel object instead of a familiar one. For the novel object recognition task, we used a Y-maze based on previous work in both mouse and rat models using perceptual and object recognition type experiments [ 40 – 42 ]. Two arms were used for this test and the third arm was permanently closed off to the animal.…”

Section: Methodsmentioning

confidence: 99%

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Immunotherapy to improve cognition and reduce pathological species in an Alzheimer’s disease mouse model

et al. 2018

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BackgroundAlzheimer’s disease (AD) is characterized by physiologically endogenous proteins amyloid beta (Aβ) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and Aβ soluble oligomers, which contain extensive β-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-β-sheet conformation antibody (aβComAb), to selectively recognize pathological Aβ and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9.MethodsIn this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18–22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks.ResultsHistological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p < 0.05). Furthermore, ELISA using oligomeric and monomeric Aβ showed a preferential affinity for oligomeric Aβ. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p < 0.01) and Aβ (p < 0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p < 0.01) and Barnes maze performance (p = 0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p < 0.05), and there was a trend for a reduction in soluble Aβ levels in the brain homogenates of female 3xTg-AD mice (p = 0.06).ConclusionsThis study shows that acute treatment with an aβComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Immunotherapy to improve cognition and reduce pathological species in an Alzheimer’s disease mouse model

et al. 2018

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“…This test has been adapted for use in rodent touchscreen chambers, enabling high‐throughput and standardised assessment of attention in rodents 23 . Three AD mouse models have been characterised using the touchscreen version of the 5CSRTT; TgCRND8 24 , TgTau P301L 25,26 and 3xTG‐AD mice 27 . These models have Aβ, tau or both Aβ and tau pathology respectively.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of attention in APP/PS1 mice shows impulsive and compulsive behaviours

Shepherd

May

Чурилов

et al. 2019

Genes Brain and Behavior

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While Alzheimer's disease (AD) is traditionally associated with deficits in episodic memory, early changes in other cognitive domains, such as attention, have been gaining interest. In line with clinical observations, some animal models of AD have been shown to develop attentional deficits, but this is not consistent across all models. The APPswe/PS1ΔE9 (APP/PS1) mouse is one of the most commonly used AD models and attention has not yet been scrutinised in this model. We set out to assess attention using the 5‐choice serial reaction time task (5CSRTT) early in the progression of cognitive symptoms in APP/PS1 mice, using clinically translatable touchscreen chambers. APP/PS1 mice showed no attentional changes across 5CSRTT training or any probes from 9 to 11 months of age. Interestingly, APP/PS1 mice showed increased impulsive and compulsive responding when task difficulty was high. This suggests that while the APP/PS1 mouse model may not be a good model of attentional changes in AD, it may be useful to study the early changes in impulsive and compulsive behaviour that have been identified in patient studies. As these changes have not previously been reported without attentional deficits in the clinic, the APP/PS1 mouse model may provide a unique opportunity to study these specific behavioural changes seen in AD, including their mechanistic underpinnings and therapeutic implications.

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“…To minimize age‐dependent changes in animals, panels with the smallest number of essential tasks could be developed to formulate a composite score specific to each type of dementia. For this purpose, not all tasks in the panel would have to be touchscreen‐based 16,28 . As to an FTD model for instance, an ideal panel could include the FR/PR test to assess motivation, the 5‐CSRTT or reversal test to measure executive functions, and the (conventional) object recognition task to evaluate episodic memory 16 .…”

Section: Limitations and Future Directionmentioning

confidence: 99%

“…This would be possible for not all tasks are relevant in certain dementia types. Using only the essential tasks would be critical if there are several treatment arms or if repetitive testing is required to assess longitudinal changes in cognition in dementia models 28,29 . Potential order effects are also a critical issue to consider in a panel approach.…”

Section: Limitations and Future Directionmentioning

confidence: 99%

Translational cognitive neuroscience of dementia with touchscreen operant chambers

Lee

Cho

Kim

2020

Genes Brain and Behavior

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Translational cognitive neuroscience of dementia involves mainly two areas: the validation of newly developed dementia animal models and the preclinical assessment of novel drug candidates in such model animals. To validate new animal models, a multidomain panel (battery) approach is essential in that dementia is, by definition, not merely a memory disorder but rather a multidomain cognitive/behavior disorder: animal modeling with a certain type of dementia would develop cognitive impairments in multiple (two at minimum) domains in a specific order according to unique spreading patterns of its neuropathology. In new drug development, the availability of highly sensitive tools assessing animal cognition is crucial to the detection of cognitive decline at the earliest stage of the disease, which may be an optimal time point to test a drug candidate. Using interspecies translatable (analogous) cognitive tasks would also be necessary to successfully predict the efficacy of drug candidates in subsequent clinical trials. Currently, this translational prediction is seriously limited given discrepancies in behavioral assessment methods between animals and humans in the preclinical and clinical trials, respectively. Since neurodegenerative diseases are often accompanied by not only cognitive but also affective and movement disorders, simultaneous assessment of task‐relevant locomotor behavior and motivation is also important to rule out the effects of potential confounders. The touchscreen operant platform may satisfy these needs by offering several advantages over conventional methodology. In this review, we discuss the touchscreen operant chamber system and highlight some of its qualities as a promising and desirable tool for translational research of dementia.

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Longitudinal evaluation of Tau‐P301L transgenic mice reveals no cognitive impairments at 17 months of age

Cited by 14 publications

References 55 publications

Immunotherapy to improve cognition and reduce pathological species in an Alzheimer’s disease mouse model

Immunotherapy to improve cognition and reduce pathological species in an Alzheimer’s disease mouse model

Evaluation of attention in APP/PS1 mice shows impulsive and compulsive behaviours

Translational cognitive neuroscience of dementia with touchscreen operant chambers

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