Female 3xTg-AD Mice Research Articles

Diffusion MRI detects longitudinal white matter changes in the 3xTg-AD mouse model of Alzheimer's disease

The sensitivity of multiple diffusion MRI (dMRI) parameters to longitudinal changes in white matter microstructure was investigated for the 3xTg-AD transgenic mouse model of Alzheimer's disease, which manifests both amyloid beta plaques and neurofibrillary tangles. By employing a specific dMRI method known as diffusional kurtosis imaging, eight different diffusion parameters were quantified to characterize distinct aspects of water diffusion. Four female 3xTg-AD mice were imaged at five time points, ranging from 4.5 to 18 months of age, and the diffusion parameters were investigated in four white matter regions (fimbria, external capsule, internal capsule and corpus callosum). Significant changes were observed in several diffusion parameters, particularly in the fimbria and in the external capsule, with a statistically significant decrease in diffusivity and a statistically significant increase in kurtosis. Our preliminary results demonstrate that dMRI can detect microstructural changes in white matter for the 3xTg-AD mouse model due to aging and/or progression of pathology, depending strongly on the diffusion parameter and anatomical region.

Sex differences in the timing behavior performance of 3xTg-AD and wild-type mice in the peak interval procedure

We investigated interval timing behavior of 10-month-old male and female 3xTg-AD mice compared with their B6129F2/J wild type controls using the peak interval procedure with a 15 s target interval. Multiple parameters reflecting different aspects of timing performance were extracted from steady-state anticipatory nose-poking behavior using two different approaches: single trial analyses and average response curve analyses. These measures can dissociate the differences in performance due to distortions in the interval timing ability or to motivational decline (i.e. apathy); both of which have been reported in Alzheimer patients. We found that the interval timing ability of male and female 3xTg-AD mice did not differ from wild-type controls. However, in measures reflecting motivational state, we found significant sex differences regardless of genotype. Specifically, female mice initiated anticipatory responding later in the trial and had lower response amplitudes than males. Although our findings can also be interpreted in terms of differences in temporal control for response initiation, they more strongly suggest the effect of differential incentive motivation between sexes on timing behavior in these mice.

Motor deficits in 16-month-old male and female 3xTg-AD mice

Motor deficits are some of the most prevalent non-cognitive symptoms of Alzheimer’s disease (AD) with patients showing impairments in speech, gait and fine motor skills. We investigated motor behaviour in 16-month-old male and female 3xTg-AD mice and their B6129SF2 wildtype (WT) controls. The 3xTg-AD mice develop extracellular Aβ plaques and tau tangles in the hippocampus and motor cortex between 6 and 9 months of age. Previously we showed that at 6 months of age, 3xTg-AD mice performed better on tests of motor coordination and motor learning than WT mice. The aim of our experiment was to use a battery of motor behaviour tests to determine if this superior motor performance was present in older mice. On the Rotarod, the aged 3xTg-AD mice showed better motor coordination and learning than WT mice. Although females performed better than males, this sex difference was confounded by body weight as females weighed less than males. There were no significant genotype or sex differences on the wire hang or grid suspension tasks, nor in stride length or stride width, but 3xTg-AD mice performed worse than WT mice on the balance beam. In comparison to the 6-month-old mice, an age-related decline in most aspects of motor behaviour was apparent. These results indicate that different sub-domains of motor function are affected differently in the 3xTg-AD mice and that aging does not have the same effect on all motor behaviours.

TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice

Alzheimer’s disease (AD) pathogenesis is a multifactorial process that involves numerous pathways within the central nervous system. Thus, interventions that interact with several disease-related pathways may offer an increased opportunity for successful prevention and treatment of AD. Translocator protein 18 kD (TSPO) is a mitochondrial protein that is associated with regulation of many cellular processes including inflammation, steroid synthesis, apoptosis, and mitochondrial respiration. Although TSPO ligands have been shown to be protective in several neurodegenerative paradigms, little work has been done to assess their potential as treatments for AD. Female 3xTg-AD mice were administered the TSPO ligand PK11195 once weekly for 5 weeks beginning at 16 months, an age characterized by extensive β-amyloid pathology and behavioral impairments. Animals treated with PK11195 showed improvements in behavior and modest reductions of in both soluble and deposited β-amyloid. The finding that short-term PK11195 treatment was effective in improving both behavioral and pathological outcomes in a model of late-stage AD supports further investigation of TSPO ligands as potential therapeutics for the treatment of AD.

Immunotherapy to improve cognition and reduce pathological species in an Alzheimer\u2019s disease mouse model

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.

Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Mouse models of Alzheimer’s disease (AD) exhibit marked differences in life expectancy depending on their genotype and sex. The assessment of frailty could provide a measure of healthspan to facilitate comparisons between different AD models. We used a validated mouse frailty index (FI) assessment tool to explore genotype and sex differences in lifespan and healthspan of 3xTg-AD mice and their B6129F2 wild-type (WT) controls. This tool is based on an approach commonly used in people and quantifies frailty by counting the accumulation of age-related health deficits. The number of deficits in an individual divided by the total number measured yields an FI score theoretically between 0 and 1, with higher scores denoting more frailty. Male 3xTg-AD mice aged 300–600 days had higher FI scores (Mean FI = 0.21 ± 0.03) than either male WT (Mean FI = 0.15 ± 0.01) or female 3xTg-AD mice (Mean FI = 0.10 ± 0.01), and the elevated frailty scores were accompanied by parallel increases in mortality. Frailty increased exponentially with age, and higher rates of deficit accumulation elevated mortality risk in all groups of mice. When mice were stratified by FI score, frailty predicted mortality, at least in females. Therefore, the mouse clinical FI provides a valuable tool for evaluating healthspan in mouse models of AD with different lifespans.

Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice

Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer’s disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12–14 months of age. Chronic sodium selenate treatment efficiently reversed hippocampal-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippocampus of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.

Abnormal circadian locomotor rhythms and Per gene expression in six-month-old triple transgenic mice model of Alzheimer’s disease

Circadian rhythm disturbance (CRD) is one of the iconic manifestations in Alzheimer’s disease (AD), a disease tightly associated with age, but the characteristics and gender difference of CRD occurred in AD have not been well demonstrated. Using 6-month-old triple transgenic AD mouse model (3xTg-AD) without obvious brain pathological changes, we demonstrated the gender difference of CRD at this age. We further showed abnormal Per gene expression in the central clock suprachiasmatic nucleus (SCN) of the 3xTg-AD mice. Specifically, compared with the wide type (WT) mice, the 3xTg-AD mice showed disrupted circadian locomotor rhythms both at LD (light-dark 12 h:12 h) and DD (constant dark) conditions, such as increased activities in the resting phase, decreased and scattered activities in the active phase, decreased overall activity intensities, amplitude, robustness, and increased intradaily variability. We further observed that 3xTg-AD female mice showed obviously less CRD compared with the 3xTg-AD male mice, and female mice of both WT and 3xTg-AD were more active in locomotor activity. Accordingly, 3xTg-AD mice showed a phase delay in the expression of Per1 and Per2 mRNA in the SCN, with the levels of Per1 and Per2 mRNA were significantly lower than that of WT mice at specific time points. We conclude that 3xTg-AD mice exhibit behavioral CRD at the age of six months with male gender preference, and these phenomena are at least partly associated with the alteration of Per1 and Per2 transcription patterns in the SCN.

Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry.

Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

Survival Curves and Behavioral Profiles ofFemale 3xTg-AD Mice Surviving to18-Months of Age as Compared toMicewith Normal Aging.

New evidence reveals a high degree of heterogeneity in Alzheimer’s disease (AD) clinical and temporal patterns, supporting the existence of several subgroups of patients. Prognosticators of end-of-life dementia specific to elderly patients are necessary to address this heterogeneity. Among 3xTg-AD mice, a widely-used model for AD, a very small number of animals overcome advanced neuropathological stages of disease beyond 18 months of age. They are usually females, which reach longevity in spite of worse neuropathological status as compared to males (the morbidity/mortality paradox). We posit that 3xTg-AD long-term survivors could serve to model end-of-life dementia but also aware about the mortality selection bias. In the present study, we performed behavioral and functional phenotype in long-term survivors, 18-month-old female 3xTg-AD mice and age-matched wildtype undergoing normal aging. Animals were followed up until natural death to correlate survival with phenotype assessments. Strong similarity of their behavioral profiles in all the variables analyzed (e.g. reflexes, sensorimotor functions, locomotion, exploration, emotionality, and anxiety-like behaviors) was found, with the exception of memory impairment, which was a salient trait in old 3xTg-AD survivors. The two groups showed similar mean life expectancy and had behavioral correlates among lifespan, neophobia and long-term memory in common, with some distinctions in 3xTg-AD, supporting recent studies in end-of-life patients. In spite of the small sample size, this brief report presents an interesting scenario to further study heterogeneity and survival in Alzheimer’s disease. 3xTg-AD survivors may be a model to gain insight into the frailty/survival paradigm in normal and pathological aging.

Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice.

Depletion of ovarian hormones at menopause is associated with increased Alzheimer’s disease (AD) risk. Hormone loss also increases central adiposity, which promotes AD development. One strategy to improve health outcomes in postmenopausal women is estrogen-based hormone therapy (HT), though its efficacy is controversial. The window of opportunity hypothesis posits that HT is beneficial only if initiated near the onset of menopause. Here, we tested this hypothesis by assessing the efficacy of HT against diet-induced obesity and AD-related pathology in female 3xTg-AD mice at early versus late middle-age. HT protected against obesity and reduced β-amyloid burden only at early middle-age. One mechanism that contributes to AD pathogenesis is microglial activation, which is increased by obesity and reduced by estrogens. In parallel to its effects on β-amyloid accumulation, we observed that HT reduced morphological evidence of microglial activation in early but not late middle-age. These findings suggest that HT may be effective during human perimenopause in reducing indices of obesity and AD-related pathology, a conclusion consistent with the window of opportunity hypothesis.

Water and T-maze protocols are equally efficient methods to assess spatial memory in 3xTg Alzheimer’s disease mice

Rodent spatial memory is commonly tested using the water-maze; however, there is a potential confound of stress on learning in this behavioural paradigm. This is particularly relevant when testing spatial memory in models of neurodegeneration, such as the 3xTg mouse model for Alzheimer’s disease. Here, we first confirmed that 3xTgAD mice express fear conditioning and then compared the performance of young and middle-aged mice on short-duration versions of the radial arm water-maze (RAWM) and the minimally stressful T-maze spontaneous alternation task. Our main questions were: (1) does the reliance on stressors in water-maze training mask the true cognitive ability of 3xTgAD mice; and (2) are 3xTgAD mice similarly impaired in water-maze and T-maze protocols. Firstly, male and female 3xTgAD mice displayed intact freezing responses in both contextual and Pavlovian fear conditions. As male 3xTgAD mice displayed relatively enhanced fear responses the remaining tests were performed using only female 3xTgAD and control mice in order to equate for response to stressors. We found that alternation rates after both short and long delays were impaired at both ages in female 3xTgAD mice, indicative of robust spatial working memory deficits. For RAWM, again performance deficits were found in young 3xTgAD mice. As both tasks had similar efficacy at revealing early spatial memory deficits, we suggest that spontaneous behavioural protocols be prioritised over water maze testing in models such the 3xTgAD mouse as the former provide a far less stressful but equally effective alternative.

Alteraciones en la corteza motora primaria en la enfermedad de Alzheimer: estudio en el modelo 3xTg-AD

IntroductionIn humans and animal models, Alzheimer disease (AD) is characterised by accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein, neuronal degeneration, and astrocytic gliosis, especially in vulnerable brain regions (hippocampus and cortex). These alterations are associated with cognitive impairment (loss of memory) and non-cognitive impairment (motor impairment). The purpose of this study was to identify cell changes (neurons and glial cells) and aggregation of Aβ and hyperphosphorylated tau protein in the primary motor cortex (M1) in 3xTg-AD mouse models at an intermediate stage of AD. MethodsWe used female 3xTg-AD mice aged 11 months and compared them to non-transgenic mice of the same age. In both groups, we assessed motor performance (open field test) and neuronal damage in M1 using specific markers: BAM10 (extracellular Aβ aggregates), tau 499 (hyperphosphorylated tau protein), GFAP (astrocytes), and Klüver-Barrera staining (neurons). ResultsFemale 3xTg-AD mice in intermediate stages of the disease displayed motor and cellular alterations associated with Aβ and hyperphosphorylated tau protein deposition in M1. ConclusionsPatients with AD display signs and symptoms of functional impairment from early stages. According to our results, M1 cell damage in intermediate-stage AD affects motor function, which is linked to progression of the disease.

Citalopram Ameliorates Impairments in Spatial Memory and Synaptic Plasticity in Female 3xTgAD Mice.

Alzheimer's disease (AD) is the primary cause of dementia. There is no effective treatment. Amyloid-β peptide (Aβ) plays an important role in the pathogenesis and thus strategies suppressing Aβ production and accumulation seem promising. Citalopram is an antidepressant drug and can decrease Aβ production and amyloid plaques in transgenic mice of AD and humans. Whether citalopram can ameliorate memory deficit was not known yet. We tested the effects of citalopram on behavioral performance and synaptic plasticity in female 3xTgAD mice, a well-characterized model of AD. Mice were treated with citalopram or water from 5 months of age for 3 months. Citalopram treatment at approximately 10 mg/kg/day significantly improved spatial memory in the Morris water maze (MWM) test, while not affecting anxiety-like and depression-like behavior in 3xTgAD mice. Further, hippocampal long-term potentiation (LTP) impairment in 3xTgAD mice was reversed by citalopram treatment. Citalopram treatment also significantly decreased the levels of insoluble Aβ40 in hippocampal and cortical tissues in 3xTgAD mice, accompanied with a reduced amyloid precursor protein (APP). Together, citalopram treatment may be a promising strategy for AD and further clinical trials should be conducted to verify the effect of citalopram on cognition in patients with AD or mild cognitive impairment.

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease

We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 µg/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve σ1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 n<smlcap>M</smlcap>), via activation of M1 and a possible involvement of σ1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 µ<smlcap>M</smlcap>) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 µg/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3β activity, p25/CDK5, neuroinflammation, soluble and insoluble Aβ₄₀, Aβ₄₂, plaques and tau pathologies. AF710B differs from conventional σ1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies.

Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-transgenic (3xTg)-AD mouse model of AD, compared with those in nontransgenic (non-Tg) controls, at 6, 8, and 14 mo of age. We found a more pronounced cortical Aβ accumulation (2- and 3.5-fold increase in Aβ42 in the soluble and insoluble protein fractions, respectively) in female 3xTg-AD mice than in the males. Furthermore, female 3xTg-AD mice displayed a significant deterioration in glucose tolerance (AUC, +118% vs. non-Tg mice at 14 mo). Fasting plasma insulin levels rose 2.5-fold from 6 to 14 mo of age in female 3xTg-AD mice. Glucose intolerance and cortical amyloid pathology worsened with age, and both were more pronounced in the females. Pancreatic amyloidopathy was revealed and could underlie the observed deficit in glycemic response in 3xTg-AD mice. The present results suggest that AD-like neuropathology extends to the pancreas in the 3xTg-AD mouse, leading to glucose intolerance and contributing to a pathologic self-amplifying loop between AD and T2D.

Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease

Which behavioral test is the most sensitive for detecting cognitive deficits in the 3xTg-AD at 6.5 months of age? The 3xTg-AD mouse model of Alzheimer's disease (AD) has three transgenes (APPswe, PS1M146V, and Tau P301L) which cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits with age. In order to determine which task is the most sensitive in the early detection of cognitive deficits, we compared male and female 3xTg-AD and B6129SF2 wildtype mice at 6.5 months of age on a test battery including spontaneous alternation in the Y-Maze, novel object recognition, spatial memory in the Barnes maze, and cued and contextual fear conditioning. The 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in the novel object recognition task nor was there a genotype difference in cued fear conditioning but females performed better than males. From our results we conclude that the 3xTg-AD mice have mild cognitive deficits in spatial learning and memory and that the Barnes maze was the most sensitive test for detecting these cognitive deficits in 6.5-month-old mice.

Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease

Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca2+ homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g., SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells.

Oxidative Stress Is a Central Target for Physical Exercise Neuroprotection Against Pathological Brain Aging.

Physical exercise is suggested for preventing or delaying senescence and Alzheimer's disease (AD). We have examined its therapeutic value in the advanced stage of AD-like pathology in 3xTg-AD female mice through voluntary wheel running from 12 to 15 months of age. Mice submitted to exercise showed improved body fitness, immunorejuvenation, improvement of behavior and cognition, and reduced amyloid and tau pathology. Brain tissue analysis of aged 3xTg-AD mice showed high levels of oxidative damage. However, this damage was decreased by physical exercise through regulation of redox homeostasis. Network analyses showed that oxidative stress was a central event, which correlated with AD-like pathology and the AD-related behaviors of anxiety, apathy, and cognitive loss. This study corroborates the importance of redox mechanisms in the neuroprotective effect of physical exercise, and supports the theory of the crucial role of oxidative stress in the switch from normal brain aging to pathological aging and AD.

Analysis of motor function in 6-month-old male and female 3xTg-AD mice

The 3xTg-AD mouse has high validity as a model of Alzheimer's disease (AD) because it develops both amyloid beta plaques and neurofibrillary tangles. Human patients with AD typically develop motor deficits, which worsen as the disease progresses, but 3xTg-AD mice have been reported to show enhanced motor abilities. We investigated the motor behaviour phenotype of male and female 3xTg-AD and B6129SF2 wildtype mice on a battery of motor behaviours at 6 months of age. Compared to wildtype mice, the 3xTg-AD mice had enhanced motor performance on the Rotarod, but worse performance on the grid suspension task. In gait analysis 3xTg-AD mice had a longer stride length and made more foot slips on the balance beam than wildtype mice. There was no overall difference in voluntary wheel-running activity between genotypes, but there was a disruption in circadian activity rhythm in 3xTg-AD mice. In some motor tasks, such as the Rotarod and balance beam, females appeared to perform better than males, but this sex differences was accounted for by differences in body weight. Our results indicate that while the 3xTg-AD mice show enhanced performance on the Rotarod, they have poorer performance on other motor behaviour tasks, indicating that their motor behaviour phenotype is more complex than previously reported. The presence of the P301L transgene may explain the enhancement of Rotarod performance but the poorer performance on other motor behaviour tasks may be due to other transgenes.