Reference and working memory deficits in the 3xTg-AD mouse between 2 and 15-months of age: A cross-sectional study

Stevens, Leanne; Brown, Richard E.

doi:10.1016/j.bbr.2014.10.033

Cited by 74 publications

(72 citation statements)

References 52 publications

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“…In contrast, if RyR channels are active prior to plasticity induction, as demonstrated in the AD models, this critical associative learning window is shortened and plasticity resilience is reduced [83,132]. Thus, in AD pathogenesis, the increased RyR activity at baseline as well as that generated from synaptic activity can blunt the critical window necessary for transforming and stabilizing long term memory formation, resulting in impaired memory performance such as that observed in 3xTgFAD mice at 2 to 3 months of age [30,98,140]. Indeed, working memory deficits are observed in young 3xTg FAD mice well before Aβ deposition [30,140] and underlying this may be a shortening of the associative learning window due to elevated Ca 2+ signaling prior to the plasticity induction [83,132].…”

Section: Ca2+ and Long And Short Term Plasticity Defects In Admentioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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Section: Ca2+ and Long And Short Term Plasticity Defects In Admentioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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“…These mice presented Aβ pathology at 6 months of age (increased Aβ40 and Aβ42 levels, intracellular accumulation of Aβ, and amyloid plaques) that preceded tau pathology with neurofibrillary tangles formation at about 12 months of age. LTP and spatial memory impairment [50–53] were also evident. In our recent studies [54], 3XTg at 8–9 months of age showed an increase of Aβ42 levels and an increase of inflammatory mediators in the hippocampus, and an impairment of cognitive functions assessed by the MWM test and the NOR test.…”

Section: Transgenic Models For the Study Of Admentioning

confidence: 99%

Rodent models for Alzheimer’s disease drug discovery

Puzzo

Gulisano

Palmeri

et al. 2015

Expert Opinion on Drug Discovery

182

113

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Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histophatological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals. Area covered This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including: APP Tg2576, APP/PS1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging. Expert opinion Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies.

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“…Superior working memory performance of male mice has been observed in the water radial-arm maze, 79 but a lack of sex differences in working memory performance has been demonstrated in the ymaze 80 and radial arm maze 81 in C57BL/6 mice. A meta-analysis in 2005 failed to find any studies demonstrating sex differences in working memory in any mouse strain, although some rat studies affirmed a male advantage.…”

Section: Tucker Et Almentioning

confidence: 99%

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

Tucker

McCabe

2016

Journal of Neurotrauma

129

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To date, clinical trials have failed to find an effective therapy for victims of traumatic brain injury (TBI) who live with motor, cognitive, and psychiatric complaints. Pre-clinical investigators are now encouraged to include male and female subjects in all translational research, which is of particular interest in the field of neurotrauma given that circulating female hormones (progesterone and estrogen) have been demonstrated to exert neuroprotective effects. To determine whether behavior of male and female C57BL6/J mice is differentially impaired by TBI, male and cycling female mice were injured by controlled cortical impact and tested for several weeks with functional assessments commonly employed in pre-clinical research. We found that cognitive and motor impairments post-TBI, as measured by the Morris water maze (MWM) and rotarod, respectively, were largely equivalent in male and female animals. However, spatial working memory, assessed by the y-maze, was poorer in female mice. Female mice were generally more active, as evidenced by greater distance traveled in the first exposure to the open field, greater distance in the y-maze, and faster swimming speeds in the MWM. Statistical analysis showed that variability in all behavioral data was no greater in cycling female mice than it was in male mice. These data all suggest that with careful selection of tests, procedures, and measurements, both sexes can be included in translational TBI research without concern for effect of hormones on functional impairments or behavioral variability.

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Reference and working memory deficits in the 3xTg-AD mouse between 2 and 15-months of age: A cross-sectional study

Cited by 74 publications

References 52 publications

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Rodent models for Alzheimer’s disease drug discovery

Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

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