Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze

Spatial learning and memory deficits in the APP23 transgenic mice have mainly been studied using the Morris water maze (MWM). However learning in the MWM relies on swimming abilities and may be confounded by the stressful nature of this test. We have therefore assessed spatial learning and memory in 12-month-old APP23 using a dry-land maze test developed by Barnes. Mice were given daily learning trials for a total of 41 successive days. After a 12-day interval the mice were re-tested for 4 additional days in order to examine the spatial memory retention. Immediately following this phase, reversal learning was examined for 13 additional days by moving the escape tunnel to the opposite position. During the initial learning phase, APP23 mice showed a significantly longer latency to find the escape tunnel as well as an increased number of errors compared to non-transgenic littermates. These deficits appeared to be due to a delay in switching from a "no strategy" to a spatial strategy. Indeed, this same delay in the use of spatial strategy was observed in the reversal phase of the study. Our results suggest that impairments in APP23 mice in learning and memory maze tests may be due to a specific deficit in the use of spatial strategy.     

Age-dependent cognitive decline in the APP23 model precedes amyloid deposition

Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6-8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-beta 1-42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-beta 1-42 peptides, but probe trial performance did correlate negatively with soluble amyloid-beta brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.     

Spatial learning,exploration, anxiety,and motor coordination in female APP23 transgenic mice with the Swedish mutation

Transgenic mice overexpressing the betaAPP gene with the Swedish mutation under the control of the murine thy-1 promoter show Alzheimer-like characteristics including the accumulation of Abeta protein in the cerebral cortex. Female 16-month-old APP23 transgenic mice were compared to age-matched non-transgenic mice in behavioral tests measuring spatial learning, exploration of environmental stimuli, anxiety, and motor coordination. APP23 transgenic mice had fewer fast ambulatory movements, either fast or slow stereotypy movements, and slow rears in a photocell activity chamber. The acquisition of spatial learning in the Morris water maze was impaired in APP23 transgenic mice, but not during the probe test or while swimming towards a visible platform. Neither were there intergroup differences in tests of anxiety or motor coordination. These results indicate that a learning deficit and hypoactivity, concordant with the early stages of Alzheimer's disease, characterize this mouse model with Abeta accumulation.     

Altered circadian locomotor activity in APP23 mice: a model for BPSD disturbances

Over the past decade, clinical Alzheimer's disease research has been challenged with an increased interest in noncognitive symptomatology, commonly referred to as behavioural and psychological signs and symptoms of dementia (BPSD). In accordance, major attention is being paid to behavioural alterations in the phenotyping of transgenic mouse models. Besides an age-dependent decline of cognitive functions, the APP23 model was previously shown to exhibit cage activity disturbances, reminiscent of diurnal rhythm disturbances in Alzheimer patients. To further scrutinize these observations, circadian patterns of horizontal locomotor activity were assessed in 3-, 6- and 12-month-old APP23 mice and wild-type littermates in a test paradigm continuously recording cage activity over a period ranging from 1 to 3 days. At the age of 3 months, APP23 profiles resembled the wild-type pattern to a large extent, although minor differences were already noticeable. Six-month-old APP23 mice displayed an altered activity profile with a first indication of increased activity during the second half of the active phase, reminiscent of sundowning behaviour in Alzheimer patients. This bimodal overnight activity pattern became even more evident at the age of 12 months. The APP23 model was therefore shown to display an age-dependent development of cage activity disturbances and sundowning-like behaviour. A comparison is made with actigraphic recordings of human Alzheimer patients exhibiting sundowning behaviour. This first report of diurnal rhythm disturbances and sundowning-like phenomena in a transgenic mouse model greatly adds to the validity of the APP23 model.     

Mood and male sexual behaviour in the APP23 model of Alzheimer's disease

Alzheimer's disease is characterised by both cognitive deterioration and the development of a wide range of neuropsychiatric disturbances, among which affective disturbances, stereotyped behaviour, dietary hyperactivity and changes in sexual behaviour. The transgenic APP23 mouse models Alzheimer's disease and has shown to be a unique tool in the study of this condition. APP23 mice develop, next to the age-dependent cognitive decline, also a range of behavioural problems, such as circadian activity disturbances and increased aggression, in analogy with the dementing patients. The present study aimed to investigate whether this model also develops mood disturbances and changes in sexual behaviour. Using two behavioural despair paradigms and the sucrose preference test, we did not find evidence for the development of depression-related behaviours. A sophisticated protocol was neither able to unravel changes in male sexual behaviour between APP23 and WT mice. The present study nevertheless provides evidence that the APP23 mice are more anxious and fearful in comparison with control littermates, which opens perspectives to future treatment studies.     

Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen

The SHIRPA primary screen comprises 40 measures covering various reflexes and basic sensorimotor functions. This multi-test battery was used to compare non-transgenic controls with APP23 transgenic mice, expressing the 751 isoform of human beta-amyloid precursor protein and characterized by amyloid deposits in parenchyma and vessel walls. The APP23 mice were distinguishable from controls by pathological limb reflexes, myoclonic jumping, seizure activity, and tail malformation. In addition, this mouse model of Alzheimer's disease was also marked by a crooked swimming trajectory. APP23 mice were also of lighter weight and were less inclined to stay immobile during a transfer arousal test. Despite the neurologic signs, APP23 transgenic mice were not deficient in stationary beam, coat-hanger, and rotorod tests, indicating intact motor coordination abilities.     

Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation

Alzheimer's disease (AD) is a progressive neurodegenerative disease clinically characterized by learning and memory function deterioration. While it is well established that exercise can improve cognitive performance in AD, there have been few basic cellular and molecular mechanisms research performed to test the interaction between exercise and AD. In this study, we aimed at investigating whether treadmill exercise improves learning and memory function in APP/PS1 transgenic mouse model of Alzheimer's disease by enhancing long-term potentiation (LTP) and up-regulation of brain-derived neurotrophic factor (BDNF) mRNA expression. Our results show that, in comparison to wild type mice, transgenic mice were characterized by impaired learning and memory function, LTP deficits and increased BDNF mRNA levels. Treadmill exercise enhanced learning and memory function not only in wild type mice but also in APP/PS1 mice paralleled by LTP. However, BDNF has emerged as a crucial regulator of synaptic plasticity mechanisms underlying learning and memory in wild-type mice, but not in APP/PS1 mice. Hence, this investigation demonstrates that treadmill exercise is an effective therapeutic that alleviate learning and memory decline in APP/PS1 mouse model, and enhanced LTP maybe a cellular mechanism involved in neuropathological course of AD and cognitive improvement induced by exercise.     

规律性运动对APP／PS1小鼠学习记忆能力的影响

目的探讨有规律的适宜运动对AD模型小鼠的学习记忆能力的影响。方法雌性C57BL／c野生型小鼠及APP／PSl转基因小鼠，经过6个月规律性运动后，测定小鼠α-分泌酶／ADAMl0活性，A8及学习记忆行为学变化。结果规律性运动6个月不仅大大提高了在野生型小鼠的学习记忆行为，而且还改善AD转基因小鼠在学习和记忆障碍，提高了在野生型小鼠及AD转基因小鼠的α-分泌酶活性，抑制Aβ40和Aβ42的产生。结论提示规律性运动可能通过增加α-分泌酶活性，抑制脑内Aβ的生成量，参与了运动对学习记忆的作用。     

Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: A longitudinal study

Transgenic animals expressing mutant human amyloid precursor protein (APP) are used as models for Alzheimer disease (AD). Ideally, behavioral tests improve the predictive validity of studies on animals by mirroring the functional impact of AD-like neuropathology. Learning and memory studies in APP transgenic models have been difficult to replicate. Standardization of procedures, automatization or improved protocol design can improve reproducibility. Here the IntelliCage, an automated system, was used for behavioral testing of APP female transgenic mice with both the Arctic and Swedish mutations, the tg-ArcSwe model. Protocols covering exploration, operant learning, place learning and extinction of place preference as well as passive avoidance tests were used for longitudinal characterization of behavior. Differences in exploratory activity were significant at four months of age, when plaque-free tg-ArcSwe mice visited less frequently the IntelliCage corners and initially performed fewer visits with licks compared to non-tg animals, inside the new environment. Fourteen months old tg-ArcSwe mice required a longer time to re-habituate to the IntelliCages than non-tg mice. At both ages tg-ArcSwe mice perseverated in place preference extinction test. Fourteen months old tg-ArcSwe mice were impaired in hippocampus-dependent spatial passive avoidance learning. This deficit was found to inversely correlate to calbindin-D28k immunoreactivity in the polymorphic layer of the dentate gyrus. Reduced water intake and body weight were observed in 4 months old tg-ArcSwe animals. The body weight difference increased with age. Thus behavioral and metabolic changes in the tg-ArcSwe APP model were detected using the IntelliCage, a system which provides the opportunity for standardized automated longitudinal behavioral phenotyping.     

Cognitive and Physical Activity Differently Modulate Disease Progression in the Amyloid Precursor Protein (APP)-23 Model of Alzheimer’s Disease

BACKGROUND: In aging mice, activity maintains hippocampal plasticity and adult hippocampal neurogenesis at a level corresponding to a younger age. Here we studied whether physical exercise and environmental enrichment would also affect brain plasticity in a mouse model of Alzheimer's disease (AD). METHODS: Amyloid precursor protein (APP)-23 mice were housed under standard or enriched conditions or in cages equipped with a running wheel. We assessed beta-amyloid plaque load, adult hippocampal neurogenesis, spatial learning, and mRNA levels of trophic factors in the brain. RESULTS: Despite stable beta-amyloid plaque load, enriched-living mice showed improved water maze performance, an up-regulation of hippocampal neurotrophin (NT-3) and brain-derived neurotrophic factor (BDNF) and increased hippocampal neurogenesis. In contrast, despite increased bodily fitness, wheel-running APP23 mice showed no change in spatial learning and no change in adult hippocampal neurogenesis but a down-regulation of hippocampal and cortical growth factors. CONCLUSIONS: We conclude that structural and molecular prerequisites for activity-dependent plasticity are preserved in mutant mice with an AD-like pathology. Our study might help explain benefits of activity for the aging brain but also demonstrates differences between physical and more cognitive activity. It also suggests a possible cellular correlate for the dissociation between structural and functional pathology often found in AD.     

Cognitive abilities of Alzheimer's disease transgenic mice are modulated by social context and circadian rhythm

In the present study, we used a new training paradigm in the intelliCage automatic behavioral assessment system to investigate cognitive functions of the transgenic mice harboring London mutation of the human amyloid precursor protein (APP.V717I). Three groups of animals: 5-, 12- and 18-24-month old were subjected to both Water Maze training and the IntelliCage-based appetitive conditioning. The spatial memory deficit was observed in all three groups of transgenic mice in both behavioral paradigms. However, the APP mice were capable to learn normally when co-housed with the wild-type (WT) littermates, in contrast to clearly impaired learning observed when the transgenic mice were housed alone. Furthermore, in the transgenic mice kept in the Intellicage alone, the cognitive deficit of the young animals was modulated by the circadian rhythm, namely was prominent only during the active phase of the day. The novel approach to study the transgenic mice cognitive abilities presented in this paper offers new insight into cognitive dysfunctions of the Alzheimer's disease mouse model.     

A Critical Time-Window for the Selective Induction of Hippocampal Memory Consolidation by a Brief Episode of Slow-Wave Sleep

Although extensively studied, the exact role of sleep in learning and memory is still not very clear. Sleep deprivation has been most frequently used to explore the effects of sleep on learning and memory, but the results from such studies are inevitably complicated by concurrent stress and distress. Furthermore, it is not clear whether there is a strict time-window between sleep and memory consolidation. In the present study we were able to induce time-locked slow-wave sleep (SWS) in mice by optogenetically stimulating GABAergic neurons in the parafacial zone (PZ), providing a direct approach to analyze the influences of SWS on learning and memory with precise time-windows. We found that SWS induced by light for 30 min immediately or 15 min after the training phase of the object-in-place task significantly prolonged the memory from 30 min to 6 h. However, induction of SWS 30 min after the training phase did not improve memory, suggesting a critical time-window between the induction of a brief episode of SWS and learning for memory consolidation. Application of a gentle touch to the mice during light stimulation to prevent SWS induction also failed to improve memory, indicating the specific role of SWS, but not the activation of PZ GABAergic neurons itself, in memory consolidation. Similar influences of light-induced SWS on memory consolidation also occurred for Y-maze spatial memory and contextual fear memory, but not for cued fear memory. SWS induction immediately before the test phase had no effect on memory performance, indicating that SWS does not affect memory retrieval. Thus, by induction of a brief-episode SWS we have revealed a critical time window for the consolidation of hippocampus-dependent memory.     

Age-dependent time course of cerebral brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 in APP23 transgenic mice

Neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), have repeatedly been shown to be involved in the pathophysiology of Alzheimer's disease (AD). Recent studies have claimed that these neurotrophic factors are important tools for therapeutic intervention in neurodegenerative diseases. So far, little is known about the age- and disease-modulated time course of cerebral neurotrophins. Therefore, we have studied protein concentrations of BDNF, NGF, and NT-3 in different brain areas and sciatic nerve, a neurotrophin-transporting peripheral nerve, in a well-characterized AD model of amyloid precursor protein-overexpressing rodents (APP23 mice) at the ages of 5.0, 10.5, and 20.0 months. In APP23 mice, there was a significant increase of BDNF and NGF in the frontal and occipital cortices (for BDNF also in the striatum) of old 20.0-month-old mice (with respect to median values up to 8.2-fold), which was highly correlated with amyloid concentrations of these brain areas. Median values of NGF and NT-3 showed up to a 6.0-fold age-dependent increase in the septum that was not detectable in APP23 mice. Hippocampus, olfactory bulb, and cerebellum (except NT-3) did not show substantial age- or genotype-related regulation of neurotrophins. In the sciatic nerve, BDNF and NGF levels are increased in5-month-old APP23 mice and decrease with age to control levels. In conclusion, APP23 mice show a genotype-dependent increase of cortical BDNF and NGF that is highly correlated with amyloid concentrations and may reflect an amyloid-related glia-derived neurotrophin secretion or an altered axonal transport of these neurotrophic factors.     

The effect of repeated rotarod training on motor skills and spatial learning ability in Lurcher mutant mice

Lurcher mutant mice represent a model of olivocerebellar degeneration. Due to loss of Purkinje cells, they suffer from functional cerebellar decortication resulting in ataxia and deterioration of cognitive functions. The aim of the work was to assess the effect of enforced physical activity represented by rotarod training on motor skills and spatial learning in young and adult B6CBA Lurcher mice. These functions were compared with those in untrained wild type mice of the same age. We examined motor skills using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Motor skills of Lurchers were found to be worse than in wild type mice, but they showed motor learning in the course of training. The training did not significantly influence the results on the bar and ladder. In the rotarod test, young trained Lurchers achieved only slightly better results than untrained ones. In adult mice, the improvement was insignificant. Lurchers failed in spatial learning test compared to the wild type mice. In the wild type mice there was no difference in learning between young and adult individuals, while young Lurchers learned better than older ones. Enforced motor activity led to spatial learning improvement in older Lurchers, but not in young ones. The experiments showed that effects of enforced physical activity in Lurcher mice mitigated the deficit in the water maze task related to age so that trained older Lurchers showed as good performance as younger ones but still worse than the wild type mice.     

Behavioral impairment of APP(V717F) mice in fear conditioning: is it only cognition?

Alzheimer's Disease (AD) is a devastating human neurodegenerative disorder associated with progressive deterioration of cognitive abilities. The APP(V717F) mouse, an animal model of AD showing robust overexpression of the human amyloid precursor protein (APP) carrying the mutation 717 V --> F, was also shown to exhibit learning and memory performance deficits. However, AD patients suffer from other abnormalities including altered emotionality. Emotionality has not been analyzed in AD mouse models. Here, motor and posture patterns exhibited by APP(V717F) mice are described in a detailed manner in fear conditioning, a paradigm that allows one to test both mnemonic and emotional characteristics of mice. Our results revealed a complex set of behavioral alterations in APP(V717F) mice in measures of exploratory behavior and fear suggesting that the effects of APP(V717F) overexpression in this mouse model are not limited to cognition and may need to be thoroughly examined in the future in a broad range of behavioral tests.     

Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice

Fmr1 knockout mice are an animal model for fragile X syndrome, the most common form of heritable mental retardation in humans. Fmr1 knockout mice exhibit macro-orchidism and cognitive and behavioural deficits reminiscent of the human phenotype. In the present study additional behavioural and cognitive testing was performed. Knockouts and control littermates were subjected to a spatial learning test using a plus-shaped water maze. Animals had to learn the position of a hidden escape platform during training trials. The position of this platform was changed during subsequent reversal trials. Previously reported deficits in reversal learning were replicated, but we also observed significant differences during the acquisition trials. A plus-shaped water maze experiment with daily changing platform positions failed to provide clear evidence for a working memory impairment, putatively underlying the spatial learning deficits. Two different test settings were used to examine the reported deficit of Fmr1 knockout mice in fear conditioning. Conditioned fear responses were observed in a contextual fear test, and the ability to acquire an emotional response was tested by means of response suppression in a conditioned emotional response procedure. Neither protocol revealed significant differences between controls and knockouts.     

Impaired Performance of Female APP/PS1 Mice in the Morris Water Maze Is Coupled with Increased Aβ Accumulation and Microglial Activation

Background: Alzheimer's disease (AD) is characterized by progressive neuronal loss and cognitive decline. Epidemiological studies suggest that the risk of AD is higher in women even when data are adjusted for age. Objective: We set out to compare changes in 9-month-old male and female mice which overexpress amyloid precursor protein (APP) with presenilin (PS1; APP/PS1 mice) and to evaluate whether any changes were coupled with deficits in spatial learning. Methods: APP/PS1 mice were assessed for their ability to learn in the Morris water maze and Aβ burden assessed by Congo Red and Aβ triple ultrasensitive assay. Neuroinflammatory changes were examined in brain tissue along with expression of Aβ-generating and Aβ-degrading enzymes. Results: A deficit in reversal phase learning in the Morris water maze was observed in female mice and was paralleled by evidence of increased accumulation of Aβ, microglial activation and expression of IL-1β. Accumulation of Aβ was coupled with an increase in expression of BACE-1 and a decrease in insulin-degrading enzyme (IDE). Conclusion: The results indicate that the observed impairment in spatial memory in female APP/PS1 mice correlated with increased Aβ burden and the changes in Aβ may have occurred as a result of enhanced BACE-1 and decreased IDE expression.     

Amyloid precursor protein knockout mice show age-dependent deficits in passive avoidance learning

Amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease (AD), but its role in cognition has been relatively little studied. APP knockout (KO) animals have been described previously and show deficits in grip strength, reduced locomotor activity and impaired learning and memory in a conditioned avoidance test and the Morris water-maze. In order to further investigate the in vivo function of APP and its proteolytic derivatives, we tested APP KO mice and age-matched wild type controls at two different ages, 3 and 8 months, in a range of behavioural tests measuring neuromuscular, locomotor and cognitive functions. These tests included the acquisition of a passive avoidance response as a measure of long-term memory of an aversive experience, and spontaneous alternation in a Y-maze, regarded as a measure of spatial short-term memory. The absence of APP expression in APP KO mice was confirmed at the protein level using hippocampal tissue in Western blotting. APP KO mice displayed deficits in forelimb grip strength and locomotor activity in agreement with previous studies. In the Y-maze test used for spontaneous alternation behaviour, APP KO animals did not exhibit reduced alternation rates. On the other hand, in the passive avoidance test, APP KO mice showed an age-related deficit in retention of memory for an aversive experience. The results suggest that APP and/or its proteolytic derivatives may play a role in long-term memory in adult brain and/or may be required during the development and maintenance of neuronal networks involved in this type of memory.     

Antisense directed at the Abeta region of APP decreases brain oxidative markers in aged senescence accelerated mice

Amyloid beta-peptide (Abeta) is known to induce free radical-mediated oxidative stress in the brain. Free radical-mediated damage to the neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of the amyloid precursor protein (APP). The senescence accelerated mouse prone 8 (SAMP8) strain was developed by phenotypic selection from a common genetic pool. The SAMP8 strain exhibits age-related deterioration in memory and learning as well as Abeta accumulation, and it is considered an effective model for studying brain aging in accelerated senescence. Previous research has shown that a phosphorothiolated antisense oligonucleotide directed against the Abeta region of APP decreases the expression of APP and reverses deficits in learning and memory in aged SAMP8 mice. Consistent with other reports, our previous study showed that 12-month-old SAMP8 mice have increased levels of oxidative stress markers in the brain compared with that in brains from 4-month-old SAMP8 mice. In the current study, 12-month-old SAMP8 mice were treated with antisense oligonucleotide directed against the Abeta region of APP, and the oxidative markers in brain were decreased significantly. Therefore, we conclude that Abeta may contribute to the oxidative stress found in aged SAMP8 mice that have learning and memory impairments. These results are discussed in reference to AD.