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Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer's disease

Scott J Webster, Adam D Bachstetter, Linda J Van Eldik

Alzheimer's Research & Therapy · 2013 · CC BY

doi:10.1186/alzrt182

Abstract

Introduction. Despite the extensive mechanistic and pathological characterization of the amyloid precursor protein (APP)/presenilin-1 (PS-1) knock-in mouse model of Alzheimer's disease (AD), very little is known about the AD-relevant behavioral deficits in this model. Characterization of the baseline behavioral performance in a variety of functional tasks and identification of the temporal onset of behavioral impairments are important to provide a foundation for future preclinical testing of AD therapeutics. Here we perform a comprehensive behavioral characterization of this model, discuss how the observed behavior correlates with the mechanistic and pathological observations of others, and compare this model with other commonly used AD mouse models.

Methods. Four different groups of mice ranging across the lifespan of this model (test groups: 7, 11, 15, and 24 months old) were run in a behavioral test battery consisting of tasks to assess motor function (grip strength, rotor rod, beam walk, open field ambulatory movement), anxiety-related behavior (open field time spent in peripheral zone vs. center zone, elevated plus maze), and cognitive function (novel object recognition, radial arm water maze).

Results. There were no differences in motor function or anxiety-related behavior between APP/PS-1 knock-in mice and wild-type counterpart mice for any age group. Cognitive deficits in both recognition memory (novel object recognition) and spatial reference memory (radial arm water maze) became apparent for the knock-in animals as the disease progressed.

Conclusion. This is the first reported comprehensive behavioral analysis of the APP/PS1 knock-in mouse model of AD. The lack of motor/coordination deficits or abnormal anxiety levels, coupled with the age/disease-related cognitive decline and high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

A large number of mouse models have been genetically engineered in attempts to model different aspects of the etiology and pathology of Alzheimer's disease (AD). While all transgenic mouse models generated to date fail to replicate completely the pathology observed in human AD, they have offered valuable insight into the molecular mechanisms of AD and have provided a useful preclinical platform with which to test potential AD therapeutics. Many of the currently used AD mouse models are generated by random exogenous insertion of genetic material into the host genome to produce overexpression of a particular protein of interest. While this approach is relatively straightforward and provides a convenient way to examine a gene/protein of interest, ectopic overexpression of a gene can lead to off-target complications unrelated to the disease process that can complicate experiments aimed at evaluating novel AD therapeutics. For example, ectopic overexpression of even a wild-type (WT) transgene can evoke cellular, anatomical, and behavioral abnormalities. One way to bypass these off-target complications common to transgenic mice is to knock-in (KI) the gene of interest into a specific genetic locus in the mouse genome.

The APPNLh/NLh × PS1P264L/P264L double gene-targeted knock-in (APP/PS1 KI) mouse takes advantage of this KI gene-targeted insertion with selective point mutations in amyloid precursor protein (APP) and presenilin-1 (PS-1) genes linked to familial AD pathology. In general, the use of the genetic KI strategy potentially increases the fidelity of a model system of a relevant disease process. A case in point is the APP/PS1 KI mouse, which replicates much of the amyloid-dependent pathologies seen clinically in AD. For example, nearly identical profiles of amyloid processing exist between observed AD patients and these APP/PS1 KI mice. Further, these mice exhibit progressive amyloid deposition starting at 6 months of age that increases linearly over time, so that by 18 months of age they show many dense amyloid deposits in regions such as the hippocampus and dentate gyrus. These amyloid depositions consist of both neuritic and non-neuritic plaques with high similarities to those seen in human AD. Other observed pathological changes for this model that are relevant to the pathogenesis of AD include: increased oxidative stress and metabolic disturbances starting as early as 1 to 2 months of age, reduction of neuronal L-type calcium channel activity in 14-month-old mice, impaired hippocampal LTP, and age-related increases in reactive gliosis and proinflammatory cytokine production.

Despite the extensive biochemical and mechanistic characterization of this APP/PS1 KI mouse model, less is known about AD-relevant behavioral/cognitive deficits of this model. One report describes cognitive deficits in 14-month-old APP/PS1 KI mice in a one-way active avoidance task. Another study showed an age-dependent cognitive impairment in a Stone T-maze task. However, to date a comprehensive behavioral analysis of this AD model has not been reported. Little is therefore known about the baseline behavioral profile and the temporal onset of behavioral impairments in this APP/PS1 KI model in a series of standard behavioral tasks. Here we seek to fill this void in knowledge by examining the cognition/behavioral profile (motor behavior, anxiety-related behavior, and cognitive function) across the lifespan of the APP/PS1 KI mouse using a cross-sectional design (age groups of 7, 11, 15, and 24 months old). We report here that the APP/PS1 KI mouse shows no motor deficits or abnormal anxiety levels at any of the ages tested. In addition, the APP/PS1 KI mouse shows an age-dependent development of cognitive deficits in two different memory domains relevant to AD: spatial reference memory and recognition memory.

Mice

Four different age groups (7, 11, 15, and 24 months) of APPNLh/NLh × PS1P264L/P264L mice were used in this study. This mouse model was originally developed at Cephalon using gene-targeted KI technology to introduce the Swedish FAD K670N/M671L point mutations, humanize the mouse β-amyloid sequence (NLh), and introduce a proline to leucine (P264L) mutation in the mouse PS-1 gene. A useful characteristic of this model is that because an endogenous promoter drives the expression of each gene, development of AD-like pathology occurs in the absence of APP or PS1 overexpression. Mice were maintained on a CD-1/129 background, and WT mice were obtained from heterozygous APP-PS1 mating pairs and maintained as a separate line for more than 20 generations of inbreeding, for use as controls. All mice were genotyped by PCR analysis of tail-snip DNA to monitor for the maintenance of the appropriate genotype.

Animal protocols followed the principles and practices outlined in the Guide for the Care and Use of Laboratory Animals, and were approved by the Institutional Animal Care and Use Committee of the University of Kentucky. All behavioral testing was performed in the University of Kentucky Rodent Behavior Core. There were no observable differences in mortality rates between genotypes in this study, and behavioral data for both genders were combined after observing no differences between the behavioral responses of male and female mice for any age group tested.

Grip strength

Forelimb grip strength was measured in grams of resistance using a digital force-gauging apparatus (Animal Grip Strength System; San Diego Instruments, San Diego, CA, USA). Forelimb strength was measured by holding the mouse by the nape of the neck and by the base of the tail. The forelimbs were placed on the tension bar pad, and the mouse was pulled back gently until it could no longer grip the bar and was forced to release its hold on the grip pad. The resistance was automatically calculated in real time with the digital force-gauging apparatus and the maximal resistance achieved by each mouse was reported as the final grip strength.

Rotor rod

The mice were placed on a rotating rod (3.18 cm diameter) in lanes 11.5 cm wide to maintain the animal in the same direction while the bar is rotating (ROTOR-ROD™ System; San Diego Instruments). The bar is 46 cm from the floor of the apparatus and the bar's speed of rotation was gradually and linearly increased from 0 to 40 rpm across the 5-minute trial. Both the latencies (seconds) and the distance (cm) at which the mice were able to maintain their balance on the bar were then recorded automatically using beam break technology.

Beam walk

The beam walk protocol used in this study has previously been described. Briefly, mice were trained to walk along an 80 cm long and 3 cm wide beam elevated 30 cm above the bench by metal supports to reach an enclosed goal box. Mice were placed on the beam at one end and allowed to traverse the beam to reach the goal box. This was repeated using decreasing size (3 cm, 2 cm, and 1 cm) beams. Foot slips were scored when one or both hind limbs slipped from the beam.

Open field activity

Mice were placed in a multi-unit open field maze (San Diego Instruments) with field chamber (50 cm long × 50 cm wide), and activity was recorded using EthoVision XT 8.0 video tracking software (Noldus Information Technology, Leesburg, VA, USA). Each 50 cm × 50 cm unit was digitally divided into 25 quadrants of equal size (nine central and 16 peripheral) using EthoVision XT 8.0 video tracking software. The nine central quadrants are collectively referred to as the center zone and the 16 peripheral quadrants are collectively referred to as the peripheral zone as previously described. Data were collected continually for 30 minutes and the distance traveled (cm), velocity (cm/second), and time spent in the center zone versus the peripheral zone were all recorded and scored automatically. The open field task is a popular model for assessing ambulatory movement and anxiety-like behaviors in response to a novel environment. Distance traveled and movement speeds are measures of ambulatory movement, whereas the amount of time spent in the center zone versus the peripheral zone is a measure of anxiety levels due to the rodent's natural thigmotaxis behavior when frightened.

Elevated plus maze

An elevated plus maze (San Diego Instruments) was used to assess anxiety-related behavior in response to a potentially dangerous environment. The elevated plus maze consists of four arms (two enclosed arms and two open arms) elevated 100 cm above the floor. Anxiety-related behavior was defined as the degree to which the subject avoided the open arms (perceived unsafe arms) of the maze, preferring the closed arms (perceived safe arm) of the maze. Each mouse was placed in the center of the maze and the amount of time spent in each arm was recorded automatically by EthoVision XT 8.0 video tracking software (Noldus Information Technology).

Radial arm water maze

The radial arm water maze (RAWM) task can be used to measure both spatial working memory and spatial reference memory. The maze procedure used in this study was designed as a rapid measure of spatial reference memory and has been previously described in detail. Briefly, the maze consisted of six arms 160 cm in diameter with arm length 30 cm and common circular swim area of 40 cm. The pool was filled with water until the level was approximately 2 cm above (covering) a clear (invisible) 10-cm circular platform. The platform was placed in the back of an arm approximately 7 cm away from the side and back walls. The pool was located in the center of a room and enclosed by a black curtain. Geometric extra-maze visual cues were fixed throughout the study on three sides of the curtains.

The RAWM protocol consisted of a 2-day testing paradigm. A staggered training schedule was used, running the mice in cohorts of five or six mice, while alternating the different cohorts through the trials over day 1 and day 2 of the test. This alternating protocol was used to avoid the learning limitations imposed by massed subsequent trials and to avoid fatigue that may result from consecutive trials. During block 1 (six trials) and block 2 (six trials), mice were trained to identify the platform location by alternating between a visible and a hidden platform in the goal arm, with three hidden platform trials and three visible platforms. Block 3 consisted of three trials all with a hidden platform. For day 2, mice were tested in three blocks of five trials each (15 total trials), with only the hidden escape platform employed, forcing the mice to use a spatial strategy to identify the goal arm location.

Data are presented as the average errors per block, similar to the methods described in, and only errors during the hidden platform trials are included in the analysis, as they represent the spatial memory component of the RAWM task. Errors were scored each time the subject entered the arm not containing the platform. An arm entry was defined as the mouse's whole body moving past the threshold of the entrance to an arm. After reaching the platform, the mouse was allowed to remain on it for 10 seconds and was then removed, dried, and placed in a warming cage until the initiation of that mouse's next trial. For each subsequent trial the mouse was released from a different start arm into the maze and allowed to locate the platform. Platform location remained constant throughout testing. RAWM performance was recorded and scored using EthoVision XT 8.0 video tracking software (Noldus Information Technology). Every arm entry for each animal was recorded and reviewed to ensure that the mice did not employ nonspatial/kinesthetic strategies (that is, chaining) to solve the task. No chaining response (defined as a mouse consecutively entering three (or more) adjacent arms to solve the task) was observed for either genotype.

Novel object recognition

This task of recognition memory utilizes the fact that animals will spend more time exploring a novel object compared with an object that they are familiar with in order to satisfy their innate curiosity/exploratory instinct. The test apparatus consisted of an open field box measuring 39.4 cm × 78.8 cm change confirmed. in diameter, and all sessions were video-recorded. On day 1 the animal was allowed to explore the open field box for a 15-minute time period. The following day the animals were each exposed to a 10-minute information session (that is, the A/A session with identical objects present). This information session was followed by a 1-hour delay during which the animals were returned to their home cages. After the delay the animals performed a 10-minute dissimilar stimuli session (A/B). The objects were made of hard plastic and had previously been counterbalanced to control for any object preference bias. The total amount of time spent with each object was recorded and scored using fully automated EthoVision XT 8.0 video tracking software (Noldus Information Technology).

The time spent was operationally defined as occurring when an animal directed its nose to the object at a distance <2.0 cm and/or by the animal touching the object with its nose or mouth. Data are presented as the D2 discrimination index. The D2 index is a common measure of discrimination between novel and familiar objects, and is considered one of the most reliable measures of discrimination because it corrects for total exploratory activity of each animal. The D2 index is calculated for an A/B session by examining the difference in time spent exploring the novel and familiar objects divided by the total exploration time for both objects:

The D2 index thus corrects for total exploratory behavior of each mouse.

Statistical analysis

All statistical analyses were performed using GraphPad Prism Version 5.00 (GraphPad Software, San Diego, CA¸USA). In the cross-sectional study design, experimental groups consisted of two genotypes at four different ages: 7 months, 11 months, 15 months, and 24 months. Each group used a ~50:50 ratio of males to females. The number of mice used per group was 5 to 12 mice per group. Unless otherwise indicated, for WT mice there were 10 aged 7 months, nine aged 11 months, five aged 15 months, and 10 aged 24 months; and for KI mice, there were nine aged 7 months, five aged 11 months, 10 aged 15 months, and five aged 24 months.

Comparison between individual experimental groups was performed by unpaired t test where appropriate. Regression analysis for RAWM and novel object recognition (NOR) cognitive data was modeled via linear regression in GraphPad with genotype, age, and errors/D2 index as independent variables and using a 95% confidence interval. Data are expressed as the mean ± the standard error of the mean. Differences between means from experimental groups were considered significant at the P <0.05 level.

Vestibulomotor behavior

The vestibulomotor behavior of APP/PS1 KI and WT control mice is presented in Figure 1. As shown in Figure 1A, no differences were observed between APP/PS1 KI and WT mice in grip strength performance. Further, the grip strength remained consistent across the age groups for both APP/PS1 KI mice and their WT counterparts.

No differences in beam walk performance were observed between genotypes or for any age group of mouse tested (Figure 1B). The number of foot slips for both APP/PS1 KI and WT mice increased as the size of the bar decreased. APP/PS1 KI mice made 1.92 ± 0.26 foot slips compared with 1.46 ± 0.37 foot slips for the WT mice crossing the 3 cm beam. For the 2 cm beam, the APP/PS1 KI mice made 9.69 ± 1.09 foot slips while the WT mice made 8.36 ± 0.70 foot slips. Figure 1B also shows the APP/PS1 KI and WT mice performance on the 1 cm beam (APP/PS1 KI mice had 20.28 ± 1.54 foot slips compared with 17.92 ± 1.00 foot slips for WT mice).

The open field behavioral task to assess ambulatory movement showed no difference between APP/PS1 KI and WT mice in distance traveled (Figure 1C) or in movement speed (Figure 1D) for any age group. Similarly, no differences in habituation behavior were observed in the open field task for either genotype or for any age group (data not shown).

Finally, no differences were observed at any age group between APP/PS1 KI and WT mice in rotor rod performance (Figure 1E), although the younger animals (7 months old) performed this task somewhat better than the older age groups. Interestingly, performance was negatively correlated with the weight of the animals (Figure 1E, insert). Specifically, WT mice performance showed a highly significant negative correlation with weight (P = 0.004), and APP/PS1 KI mice showed a similar pattern that did not reach statistical significance (P = 0.052).

Anxiety-related behavior

The anxiety-related behavior of APP/PS1 KI and WT mice was assessed by two behavioral tests: analysis of time spent in the center zone versus peripheral zone of the open field arena; and the elevated plus maze task. As shown in Figure 2A, no differences were seen between APP/PS1 KI and WT mice, or between any age group of mice, in the amount of time each mouse spent in the open center zone of the open field behavioral task. Similarly, in the elevated plus maze task, both the APP/PS1 KI and WT mice spent more time in the enclosed arms compared with the open arms, and this was consistent across all age groups (Figure 2B). No significant differences were observed between APP/PS1 KI and WT mice at any age.

Cognitive behavior

The cognitive behavior of APP/PS1 KI and WT mice was tested in the RAWM and NOR behavioral tasks - tests that measure spatial reference memory and recognition memory, respectively.

In the RAWM, there was no difference in performance between APP/PS1 KI mice and WT mice at 7 months of age (Figure 3A). In contrast, APP/PS1 KI mice aged 11 months old (Figure 3B), 15 months old (Figure 3C), and 24 months old (Figure 3D) performed significantly worse in the RAWM task than did the WT mice of the same ages. When the RAWM maze data are analyzed as a function of errors made versus age of the animals (Figure 3E), it is evident that APP/PS1 KI mice progressively increase the number of errors they make as they age (and the disease progresses).

In the NOR behavior task, the APP/PS1 KI and WT mice both showed a clear preference for novel object exploration during the dissimilar stimuli (A/B) session compared with the familiar at the ages of 7 and 11 months old (Figure 3F). However, in the groups of 15 and 24 month olds, the APP/PS1 KI mice lost the ability to discriminate between familiar and novel objects and were significantly impaired compared with the WT controls (P = 0.044 for 15 month olds, P = 0.041 for 24 month olds). Each animal tested had an exploration time >10 seconds with each object, and no significant difference in movement speed (velocity range: 2.4 to 3.6 cm/second) was observed between genotypes or age groups. When the NOR task data are analyzed as a function of the D2 recognition index versus age of the animals (Figure 3G), it is evident that APP/PS1 KI mice also become progressively impaired in this task as they age and the AD-relevant pathology progresses.

Discussion

Many lines of genetically altered mice have been generated during the past few decades in an effort to better understand the pathogenesis of AD. These mouse models of AD pathobiology have provided significant neuropathological, biochemical, physiological, and behavioral insights into AD pathogenesis. Many of the AD mouse models differ in the site of the mutation in APP, or in the number of APP mutations in one mouse, or the addition of mutations in PS1 or tau. In general, the genetic differences result in each mouse model having a unique pathobiology that makes it acutely useful for preclinical testing of a particular type of AD-relevant therapeutics. For example, if the mechanism of action of a specific preclinical therapeutic is to decrease cytokine overproduction, then a mouse model that demonstrates cytokine overproduction is needed for accurate testing of the therapeutic.

Improvements in behavioral endpoints are often the gold standard used to demonstrate efficacy of preclinical therapeutics. However, for such endpoints to be useful, it is necessary to know when cognitive deficits reproducibly develop in the AD mouse model in relation to the particular druggable target of interest. As shown in Figure 4, the temporal time courses can be quite different between commonly used models. In addition, some behavioral tasks are clearly more sensitive to cognitive deficit detection at earlier ages. Figure 4 also shows how noncognitive behaviors, such as increased activity in motor tasks, should be considered in the selection of the most appropriate preclinical model to use for a particular study, because these noncognitive behaviors may interfere with the interpretation of cognitive tasks.

To assess the onset and progression of the cognitive impairments in the APP/PS1 KI mouse model, we have performed a comprehensive behavioral analysis across the lifespan of this model from 7 to 24 months old. Our data document clear age-dependent cognitive deficits in the APP/PS1 KI mice in both recognition memory (NOR) and spatial reference memory (RAWM) that become more prominent with increasing age. Further, in Figure 4 we compare the APP/PS1 KI mouse model with other AD mouse models in regard to the onset/progression of AD-relevant impairments in motor function, anxiety-related behavior, and cognition in an attempt to clarify how the APP/PS1 KI model fits into the growing literature on modeling AD in rodents. The data presented here for motor function, anxiety-related behavior, and cognitive deficits are critically important to the future application and utility of this model in preclinical testing of AD-relevant therapeutics by: establishing baseline behavioral characteristics of this model; and providing valuable information helpful in appropriate study design. These are important observations, as they establish baseline motor function and anxiety behavior, which is important to know in any mouse model prior to assessing cognitive functioning to avoid unwanted confounds.

In contrast to a number of the mice strains shown in Figure 4, which were found to have motor impairment and hyperactivity, the APP/PS1 KI mice exhibit no differences in ambulatory movement, grip strength, or coordination when compared with WT controls at any of the ages tested. There were also no anxiety-related behavior deficits seen at any age in the APP/PS1 KI mice in the elevated plus maze tasks. This is in contrast to the Tg2576, J20, APP/PS1, and 5xFAD mice, which all were found to have increased anxiety-related behavior in the elevated plus maze task. In the open field task, animals with elevated anxiety levels will spend little time exploring the center of the chamber. The APP/PS1 KI mice do not exhibit anxiety-related behavior, as they showed normal exploration of the center of the open field chamber. Anxiety behavior did not differ between APP/PS1 KI mice and WT mice for any age tested. Our results therefore demonstrate that there are no deficits in either motor function or anxiety levels that could potentially confound cognitive testing in this mouse model of AD, which is dissimilar to the majority of the mouse models shown in Figure 4.

Attempts to model AD-relevant cognitive deficits in mouse models have met with some degree of success. Reference memory is a type of memory that is often assessed in various mouse models of AD because deficits in this type of memory are highly specific for hippocampal function (one of the earliest/most severely affected brain regions in human AD). One common method for assessing deficits in hippocampal-based reference memory is through the use of exploration-based memory tasks such as the Morris water maze and the RAWM. Here we observe deficits in spatial reference memory for the APP/PS1 KI mice when tested in the RAWM. These deficits in spatial reference memory are first evident in the 11 month age group, and continue to progress as the age/pathology increases in this model. The temporal onset and progression of cognitive impairment compared with other commonly used AD mouse models can be seen in Figure 4. For example, compared with other APP and PS1 AD mouse models, such as the APP/PS1 model and the APP + PS1 model, the onset of cognitive deficits in the APP/PS1 KI model appears to occur slightly later in life. Both the APP + PS1 model and the APP/PS1 model show deficits at 4 to 6 months of age, whereas the APP/PS1 KI mice show deficits starting at 11 months old (Figure 3).

Another commonly tested type of AD-relevant memory is that of recognition memory. The most common way to assess recognition memory in mice is through the use of the NOR task. Here we see cognitive impairment in the NOR task manifest in the APP/PS1 KI model at 15 months of age. As shown in Figure 4, this temporal pattern is similar to the onset of NOR deficits in some other AD mouse models, such as the Tg2576 mice and the APP + PS1 model. In contrast, some mouse models such as the PDAPP, APP23, TgCRND8, J20, 5xFAD, and 3xTG-AD mice show impairment in recognition memory at a younger age. Overall, for many of the AD mouse models it appears that deficits in spatial working memory (Morris water maze and RAWM) become apparent earlier than deficits in recognition memory (NOR).

With regard to β-amyloid, similar to other commonly used models of AD such as the Tg2576 mouse and the 5xFAD mouse, in the APP/PS1 KI model the amyloid burden occurs prior to the onset of cognitive deficits. Other potential therapeutic targets such as elevated levels of oxidative stress and neuroinflammation also occur before the observable cognitive deficits in the APP/PS1 KI mouse model. With respect to oxidative stress, the APP/PS1 KI mouse model is also considerably different from other models such as the Tg2576 and 3xTG-AD mice in the magnitude and temporal time course of oxidative stress. Elevated levels of oxidative stress have been linked to the cognitive deficits seen in AD. In a study of the APP/PS1 KI mice, NADPH oxidase (a marker of oxidative stress) was reported to increase with the age of the animal and correlate with increased β-amyloid levels. Further, this same study reported that NADPH oxidase is correlated with APP/PS1 KI behavioral performance in the Stone T-maze, with lower levels of NADPH oxidase and slight deficits observable at 4 to 6 months of age and both becoming more pronounced by 16 to 19 months of age. This provides an example of how the APP/PS1 KI mouse could be a useful model to test preclinical therapeutics targeted at reducing oxidative stress.

AD is a very complex disease, with many interrelated mechanisms and pathologies occurring concomitantly. Although no animal model fully replicates the human disease, AD mouse models are useful to investigate different aspects of AD pathology and disease progression. AD mouse models have been invaluable in advancing our understanding of disease mechanisms and in preclinical testing of potential therapeutics. Paramount to the selection of the appropriate model for evaluation of potential therapeutic interventions is demonstration that the desired relevant target for the preclinical therapeutic is present in the model at a therapeutically relevant time. For example, the APP/PS1 KI model used here is an ideal model for assessing the pathogenesis and effects of early oxidative stress or dysregulated neuroinflammation as we recently showed. In contrast, the APP/PS1 KI model lacks AD-relevant tau pathology. This model would therefore be inappropriate to examine topics relating to the effect of microtubule-associated tau disruption in AD. Instead, a model such as the 3xTG-AD mouse (or another relevant model showing tau pathology) should be selected instead. Similarly, if AD-related motor deficits are the target of research interest, selection of an appropriate model (Figure 4) showing motor deficits such as the Tg2576 or 5xFAD mouse would be salient, whereas a model like the APP/PS1 KI model that does not develop motor deficits would not be useful. Conversely, if AD-related cognitive deficits are of interest, then motor deficits need to be accounted for, or else a model that lacks motor deficits but that displays cognitive impairment should be selected so as to eliminate possible motor related confounds.

Each transgenic mouse model of AD provides different insights into aspects of AD pathology and progression. Careful forethought is therefore required in the selection of an optimal model based on specific research interests. Our hope is that, with regard to motor and cognitive deficits relating to AD, the discussion and Figure 4 presented here can help in the selection of the ideal model by providing an overview of the development and time course of behavioral deficits in the commonly used mouse models of AD.

Conclusion

This study is the first comprehensive behavioral analysis reported for the APP/PS1 KI mouse model of AD and the results presented here add to a growing literature for this model. The lack of any motor/coordination deficits or abnormal anxiety levels, coupled with an age/disease-related cognitive decline and the high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics.

Abbreviations

AD: Alzheimer's disease; APP: amyloid precursor protein; D2: discrimination index; KI: knock-in; NADPH: nicotinamide adenine dinucleotide phosphate; NOR: novel object recognition; PS-1: presenilin-1; RAWM: radial arm water maze; WT: wild type

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

SJW participated in the design of the research studies, performed the behavioral tests, and drafted the manuscript. ADB participated in the design of the study, performed the statistical analyses, and helped analyze data and draft the manuscript. LJVE conceived of the study, participated in its design and coordination, and helped write the manuscript. All authors read and approved the final manuscript.

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    Thibault O Pancani T Landfield PW Norris CM Reduction in neuronal L-type calcium channel activity in a double knock-in mouse model of Alzheimer's diseaseBiochim Biophys Acta2012 1822546549

    Not in our library10.1016/j.bbadis.2012.01.004

  17. 17.

    Bachstetter AD Norris CM Sompol P Wilcock DM Goulding D Neltner JH St Clair D Watterson DM Van Eldik LJ Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathologyJ Neurosci2012 321020110210

    Not in our library10.1523/jneurosci.1496-12.2012

  18. 18.

    Bruce-Keller AJ Gupta S Knight AG Beckett TL McMullen JM Davis PR Murphy MP Van Eldik LJ St Clair D Keller JN Cognitive impairment in humanized APP × PS1 mice is linked to Aβ(1-42) and NOX activationNeurobiol Dis2011 44317326

    Not in our library10.1016/j.nbd.2011.07.012

  19. 19.

    Zhang R Xue G Wang S Zhang L Shi C Xie X Novel object recognition as a facile behavior test for evaluating drug effects in AβPP/PS1 Alzheimer's disease mouse modelJ Alzheimers Dis2012 31801812

    Not in our library10.3233/jad-2012-120151

  20. 20.

    Barker GR Warburton EC When is the hippocampus involved in recognition memory?J Neurosci2011 311072110731

    Not in our library10.1523/jneurosci.6413-10.2011

  21. 21.

    Diamond DM Park CR Heman KL Rose GM Exposing rats to a predator impairs spatial working memory in the radial arm water mazeHippocampus1999 9542552

    Not in our library10.1002/(sici)1098-1063(1999)9:5<542::aid-hipo8>3.0.co;2-n

  22. 22.

    Anantharaman M Tangpong J Keller JN Murphy MP Markesbery WR Kiningham KK St Clair DK Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH × PS-1P264L/P264L double knock-in mouse model of Alzheimer's diseaseAm J Pathol2006 16816081618

    Not in our library10.2353/ajpath.2006.051223

  23. 23.

    Tsenter J Beni-Adani L Assaf Y Alexandrovich AG Trembovler V Shohami E Dynamic changes in the recovery after traumatic brain injury in mice: effect of injury severity on T2-weighted MRI abnormalities, and motor and cognitive functionsJ Neurotrauma2008 25324333

    Not in our library10.1089/neu.2007.0452

  24. 24.

    Liu X Wu R Tai F Ma L Wei B Yang X Zhang X Jia R Effects of group housing on stress induced emotional and neuroendocrine alterationsBrain Res2013 15027180

    Not in our library10.1016/j.brainres.2013.01.044

  25. 25.

    Prut L Belzung C The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a reviewEur J Pharmacol2003 463333

    Not in our library10.1016/s0014-2999(03)01272-x

  26. 26.

    Sood A Warren Beach J Webster SJ Terry AV Buccafusco JJ The effects of JWB1-84-1 on memory-related task performance by amyloid Aβ transgenic mice and by young and aged monkeysNeuropharmacology2007 53588600

    Not in our library10.1016/j.neuropharm.2007.06.028

  27. 27.

    Arendash GW King DL Gordon MN Morgan D Hatcher JM Hope CE Diamond DM Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenesBrain Res2001 8914253

    Not in our library10.1016/s0006-8993(00)03186-3

  28. 28.

    Alamed J Wilcock DM Diamond DM Gordon MN Morgan D Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic miceNat Protoc2006 116711679

    Not in our library10.1038/nprot.2006.275

  29. 29.

    Sik A van Nieuwehuyzen P Prickaerts J Blokland A Performance of different mouse strains in an object recognition taskBehav Brain Res2003 1474954

    Not in our library10.1016/s0166-4328(03)00117-7

  30. 30.

    Rodriguiz RM Wetsel WC Levin ED, Buccafusco JJAssessments of cognitive deficits in mutant miceAnimal Models of Cognitive Impairment2006 Boca Raton, FL

    Not in our library

  31. 31.

    Crawley JN Behavioral phenotyping strategies for mutant miceNeuron2008 57809818

    Not in our library10.1016/j.neuron.2008.03.001

  32. 32.

    Kliethermes CL Cronise K Crabbe JC Anxiety-like behavior in mice in two apparatuses during withdrawal from chronic ethanol vapor inhalationAlcohol Clin Exp Res2004 2810121019

    Not in our library10.1097/01.alc.0000131976.40428.8f

  33. 33.

    Bryan KJ Lee H Perry G Smith MA Casadesus G Buccafusco JJ. Boca Raton, FLTransgenic mouse models of Alzheimer's disease: behavioral testing and considerationsMethods of Behavior Analysis in Neuroscience2009 2

    Not in our library

  34. 34.

    Kobayashi DT Chen KS Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer's diseaseGenes Brain Behav2005 4173196

    Not in our library10.1111/j.1601-183x.2005.00124.x

  35. 35.

    West MJ Regionally specific loss of neurons in the aging human hippocampusNeurobiol Aging1993 14287293

    Not in our library10.1016/0197-4580(93)90113-p

  36. 36.

    Park JH Widi GA Gimbel DA Harel NY Lee DH Strittmatter SM Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer's transgenic miceJ Neurosci2006 261327913286

    Not in our library10.1523/jneurosci.4504-06.2006

  37. 37.

    Trinchese F Liu S Battaglia F Walter S Mathews PM Arancio O Progressive age-related development of Alzheimer-like pathology in APP/PS1 miceAnn Neurol2004 55801814

    Not in our library10.1002/ana.20101

  38. 38.

    McKenna JT Christie MA Jeffrey BA McCoy JG Lee E Connolly NP Ward CP Strecker RE Chronic ramelteon treatment in a mouse model of Alzheimer's diseaseArch Ital Biol2012 150514

    Not in our library10.4449/aib.v149i5.1375

  39. 39.

    Nagakura A Shitaka Y Yarimizu J Matsuoka N Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantineEur J Pharmacol2013 7035361

    Not in our library10.1016/j.ejphar.2012.12.023

  40. 40.

    Westerman MA Cooper-Blacketer D Mariash A Kotilinek L Kawarabayashi T Younkin LH Carlson GA Younkin SG Ashe KH The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer's diseaseJ Neurosci2002 2218581867

    Not in our library10.1523/jneurosci.22-05-01858.2002

  41. 41.

    Hall AM Roberson ED Mouse models of Alzheimer's diseaseBrain Res Bull2012 88312

    Not in our library10.1016/j.brainresbull.2011.11.017

  42. 42.

    Kimura R Ohno M Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse modelNeurobiol Dis2009 33229235

    Not in our library10.1016/j.nbd.2008.10.006

  43. 43.

    Ohno M Cole SL Yasvoina M Zhao J Citron M Berry R Disterhoft JF Vassar R BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic miceNeurobiol Dis2007 26134145

    Not in our library10.1016/j.nbd.2006.12.008

  44. 44.

    Abdul HM Sultana R St Clair DK Markesbery WR Butterfield DA Oxidative damage in brain from human mutant APP/PS-1 double knock-in mice as a function of ageFree Radic Biol Med2008 4514201425

    Not in our library10.1016/j.freeradbiomed.2008.08.012

  45. 45.

    Pratico D Uryu K Leight S Trojanoswki JQ Lee VM Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosisJ Neurosci2001 2141834187

    Not in our library10.1523/jneurosci.21-12-04183.2001

  46. 46.

    Smith MA Hirai K Hsiao K Pappolla MA Harris PL Siedlak SL Tabaton M Perry G Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stressJ Neurochem1998 7022122215

    Not in our library10.1046/j.1471-4159.1998.70052212.x

  47. 47.
    Age-related loss of phospholipid asymmetry in APPNLh/APPNLh x PS-1P264L/PS-1P264L human double mutant knock-in mice: Relevance to Alzheimer disease · 2010
    Not checked
  48. 48.

    Yao J Irwin RW Zhao L Nilsen J Hamilton RT Brinton RD Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's diseaseProc Natl Acad Sci USA2009 1061467014675

    Not in our library10.1073/pnas.0903563106

  49. 49.

    Kim HA Miller AA Drummond GR Thrift AG Arumugam TV Phan TG Srikanth VK Sobey CG Vascular cognitive impairment and Alzheimer's disease: role of cerebral hypoperfusion and oxidative stressNaunyn Schmiedebergs Arch Pharmacol2012 385953959

    Not in our library10.1007/s00210-012-0790-7

  50. 50.
    Antioxidant Therapies for Alzheimer's Disease · 2012
    No notice
  51. 51.

    Scarmeas N Hadjigeorgiou GM Papadimitriou A Dubois B Sarazin M Brandt J Albert M Marder K Bell K Honig LS Wegesin D Stern Y Motor signs during the course of Alzheimer diseaseNeurology2004 63975982

    Not in our library10.1212/01.wnl.0000138440.39918.0c

  52. 52.

    Dodart JC Meziane H Mathis C Bales KR Paul SM Ungerer A Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor proteinBehav Neurosci1999 113982990

    Not in our library10.1037//0735-7044.113.5.982

  53. 53.

    Nilsson LN Arendash GW Leighty RE Costa DA Low MA Garcia MF Cracciolo JR Rojiani A Wu X Bales KR Paul SM Potter H Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formationNeurobiol Aging2004 2511531167

    Not in our library10.1016/j.neurobiolaging.2003.12.011

  54. 54.

    Hartman RE Izumi Y Bales KR Paul SM Wozniak DF Holtzman DM Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's diseaseJ Neurosci2005 2562136220

    Not in our library10.1523/jneurosci.0664-05.2005

  55. 55.

    Chen G Chen KS Knox J Inglis J Bernard A Martin SJ Justice A McConlogue L Games D Freedman SB Morris RG A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's diseaseNature2000 408975979

    Not in our library10.1038/35050103

  56. 56.

    Daumas S Sandin J Chen KS Kobayashi D Tulloch J Martin SJ Games D Morris RG Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: deficit in memory retrieval associated with increased sensitivity to interference?Learn Mem2008 15625632

    Not in our library10.1101/lm.990208

  57. 57.

    Dodart JC Bales KR Gannon KS Greene SJ DeMattos RB Mathis C DeLong CA Wu S Wu X Holtzman DM Paul SM Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease modelNat Neurosci2002 5452457

    Not in our library10.1038/nn842

  58. 58.

    Dineley KT Xia X Bui D Sweatt JD Zheng H Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteinsJ Biol Chem2002 2772276822780

    Not in our library10.1074/jbc.m200164200

  59. 59.

    Chapman PF White GL Jones MW Cooper-Blacketer D Marshall VJ Irizarry M Younkin L Good MA Bliss TV Hyman BT Younkin SG Hsiao KK Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic miceNat Neurosci1999 2271276

    Not in our library10.1038/6374

  60. 60.

    Arendash GW Lewis J Leighty RE McGowan E Cracchiolo JR Hutton M Garcia MF Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's disease: linkage of poorer cognitive performance to tau pathology in forebrainBrain Res2004 10122941

    Not in our library10.1016/j.brainres.2004.02.081

  61. 61.

    King DL Arendash GW Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 monthsPhysiol Behav2002 75627642

    Not in our library10.1016/s0031-9384(02)00639-x

  62. 62.

    Arendash GW Gordon MN Diamond DM Austin LA Hatcher JM Jantzen P DiCarlo G Wilcock D Morgan D Behavioral assessment of Alzheimer's transgenic mice following long-term Aβ vaccination: task specificity and correlations between Aβ deposition and spatial memoryDNA Cell Biol2001 20737744

    Not in our library10.1089/10445490152717604

  63. 63.

    King DL Arendash GW Crawford F Sterk T Menendez J Mullan MJ Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's diseaseBehav Brain Res1999 103145162

    Not in our library10.1016/s0166-4328(99)00037-6

  64. 64.

    Lalonde R Lewis TL Strazielle C Kim H Fukuchi K Transgenic mice expressing the betaAPP695SWE mutation: effects on exploratory activity, anxiety, and motor coordinationBrain Res2003 9773845

    Not in our library10.1016/s0006-8993(03)02694-5

  65. 65.

    Lassalle JM Halley H Daumas S Verret L Frances B Effects of the genetic background on cognitive performances of TG2576 miceBehav Brain Res2008 191104110

    Not in our library10.1016/j.bbr.2008.03.017

  66. 66.

    Gil-Bea FJ Aisa B Schliebs R Ramirez MJ Increase of locomotor activity underlying the behavioral disinhibition in tg2576 miceBehav Neurosci2007 121340344

    Not in our library10.1037/0735-7044.121.2.340

  67. 67.

    Ognibene E Middei S Daniele S Adriani W Ghirardi O Caprioli A Laviola G Aspects of spatial memory and behavioral disinhibition in Tg2576 transgenic mice as a model of Alzheimer's diseaseBehav Brain Res2005 156225232

    Not in our library10.1016/j.bbr.2004.05.028

  68. 68.

    Corcoran KA Lu Y Turner RS Maren S Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's diseaseLearn Mem2002 9243252

    Not in our library10.1101/lm.51002

  69. 69.

    Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic miceScience1996 27499102

    Not in our library10.1126/science.274.5284.99

  70. 70.

    Ohno M Sametsky EA Younkin LH Oakley H Younkin SG Citron M Vassar R Disterhoft JF BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's diseaseNeuron2004 412733

    Not in our library10.1016/s0896-6273(03)00810-9

  71. 71.

    Morgan D Diamond DM Gottschall PE Ugen KE Dickey C Hardy J Duff K Jantzen P DiCarlo G Wilcock D Connor K Hatcher J Hope C Gordon M Arendash GW A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's diseaseNature2000 408982985

    Not in our library10.1038/35050116

  72. 72.

    Yassine N Lazaris A Dorner-Ciossek C Despres O Meyer L Maitre M Mensah-Nyagan AG Cassel JC Mathis C Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer miceNeurobiol Aging2013 34716730

    Not in our library10.1016/j.neurobiolaging.2012.06.016

  73. 73.

    Oules B Del Prete D Greco B Zhang X Lauritzen I Sevalle J Moreno S Paterlini-Brechot P Trebak M Checler F Benfenati F Chami M Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer diseaseJ Neurosci2012 321182011834

    Not in our library10.1523/jneurosci.0875-12.2012

  74. 74.

    Van Dam D D'Hooge R Staufenbiel M Van Ginneken C Van Meir F De Deyn PP Age-dependent cognitive decline in the APP23 model precedes amyloid depositionEur J Neurosci2003 17388396

    Not in our library10.1046/j.1460-9568.2003.02444.x

  75. 75.

    Kelly PH Bondolfi L Hunziker D Schlecht HP Carver K Maguire E Abramowski D Wiederhold KH Sturchler-Pierrat C Jucker M Bergmann R Staufenbiel M Sommer B Progressive age-related impairment of cognitive behavior in APP23 transgenic miceNeurobiol Aging2003 24365378

    Not in our library10.1016/s0197-4580(02)00098-2

  76. 76.

    Huang SM Mouri A Kokubo H Nakajima R Suemoto T Higuchi M Staufenbiel M Noda Y Yamaguchi H Nabeshima T Saido TC Iwata N Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive functionJ Biol Chem2006 2811794117951

    Not in our library10.1074/jbc.m601372200

  77. 77.

    Heneka MT Ramanathan M Jacobs AH Dumitrescu-Ozimek L Bilkei-Gorzo A Debeir T Sastre M Galldiks N Zimmer A Hoehn M Heiss WD Klockgether T Staufenbiel M Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic miceJ Neurosci2006 2613431354

    Not in our library10.1523/jneurosci.4236-05.2006

  78. 78.

    Prut L Abramowski D Krucker T Levy CL Roberts AJ Staufenbiel M Wiessner C Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes mazeBehav Brain Res2007 179107110

    Not in our library10.1016/j.bbr.2007.01.017

  79. 79.

    Lalonde R Dumont M Staufenbiel M Sturchler-Pierrat C Strazielle C Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutationBrain Res2002 9563644

    Not in our library10.1016/s0006-8993(02)03476-5

  80. 80.

    Lalonde R Dumont M Staufenbiel M Strazielle C Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screenBehav Brain Res2005 1579198

    Not in our library10.1016/j.bbr.2004.06.020

  81. 81.

    Dumont M Strazielle C Staufenbiel M Lalonde R Spatial learning and exploration of environmental stimuli in 24-month-old female APP23 transgenic mice with the Swedish mutationBrain Res2004 1024113121

    Not in our library10.1016/j.brainres.2004.07.052

  82. 82.

    Hyde LA Kazdoba TM Grilli M Lozza G Brusa R Zhang Q Wong GT McCool MF Zhang L Parker EM Higgins GA Age-progressing cognitive impairments and neuropathology in transgenic CRND8 miceBehav Brain Res2005 160344355

    Not in our library10.1016/j.bbr.2004.12.017

  83. 83.

    Touma C Ambree O Gortz N Keyvani K Lewejohann L Palme R Paulus W Schwarze-Eicker K Sachser N Age- and sex-dependent development of adrenocortical hyperactivity in a transgenic mouse model of Alzheimer's diseaseNeurobiol Aging2004 25893904

    Not in our library10.1016/j.neurobiolaging.2003.09.004

  84. 84.

    Ambree O Richter H Sachser N Lewejohann L Dere E de Souza Silva MA Herring A Keyvani K Paulus W Schabitz WR Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer's diseaseNeurobiol Aging2009 3011921204

    Not in our library10.1016/j.neurobiolaging.2007.11.010

  85. 85.

    Hanna A Iremonger K Das P Dickson D Golde T Janus C Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosisAlzheimers Res Ther2012 421

    Not in our library10.1186/alzrt124

  86. 86.

    Chishti MA Yang DS Janus C Phinney AL Horne P Pearson J Strome R Zuker N Loukides J French J Turner S Lozza G Grilli M Kunicki S Morissette C Paquette J Gervais F Bergeron C Fraser PE Carlson GA George-Hyslop PS Westaway D Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695J Biol Chem2001 2762156221570

    Not in our library10.1074/jbc.m100710200

  87. 87.

    Janus C Pearson J McLaurin J Mathews PM Jiang Y Schmidt SD Chishti MA Horne P Heslin D French J Mount HT Nixon RA Mercken M Bergeron C Fraser PE St George-Hyslop P Westaway D A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's diseaseNature2000 408979982

    Not in our library10.1038/35050110

  88. 88.

    Gortz N Lewejohann L Tomm M Ambree O Keyvani K Paulus W Sachser N Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer miceBehav Brain Res2008 1914348

    Not in our library10.1016/j.bbr.2008.03.006

  89. 89.

    Richter H Ambree O Lewejohann L Herring A Keyvani K Paulus W Palme R Touma C Schabitz WR Sachser N Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom?Behav Brain Res2008 1907484

    Not in our library10.1016/j.bbr.2008.02.005

  90. 90.

    Bellucci A Luccarini I Scali C Prosperi C Giovannini MG Pepeu G Casamenti F Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 miceNeurobiol Dis2006 23260272

    Not in our library10.1016/j.nbd.2006.03.012

  91. 91.

    Lovasic L Bauschke H Janus C Working memory impairment in a transgenic amyloid precursor protein TgCRND8 mouse model of Alzheimer's diseaseGenes Brain Behav2005 4197208

    Not in our library10.1111/j.1601-183x.2004.00104.x

  92. 92.

    Janus C Search strategies used by APP transgenic mice during navigation in the Morris water mazeLearn Mem2004 11337346

    Not in our library10.1101/lm.70104

  93. 93.

    Hanna A Horne P Yager D Eckman C Eckman E Janus C Amyloid beta and impairment in multiple memory systems in older transgenic APP TgCRND8 miceGenes Brain Behav2009 8676684

    Not in our library10.1111/j.1601-183x.2009.00510.x

  94. 94.

    Harris JA Devidze N Halabisky B Lo I Thwin MT Yu GQ Bredesen DE Masliah E Mucke L Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor proteinJ Neurosci2010 30372381

    Not in our library10.1523/jneurosci.5341-09.2010

  95. 95.

    Cheng IH Scearce-Levie K Legleiter J Palop JJ Gerstein H Bien-Ly N Puolivali J Lesne S Ashe KH Muchowski PJ Mucke L Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse modelsJ Biol Chem2007 2822381823828

    Not in our library10.1074/jbc.m701078200

  96. 96.

    Sanchez-Mejia RO Newman JW Toh S Yu GQ Zhou Y Halabisky B Cisse M Scearce-Levie K Cheng IH Gan L Palop JJ Bonventre JV Mucke L Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's diseaseNat Neurosci2008 1113111318

    Not in our library10.1038/nn.2213

  97. 97.

    Saura CA Chen G Malkani S Choi SY Takahashi RH Zhang D Gouras GK Kirkwood A Morris RG Shen J Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic miceJ Neurosci2005 2567556764

    Not in our library10.1523/jneurosci.1247-05.2005

  98. 98.

    Lustbader JW Cirilli M Lin C Xu HW Takuma K Wang N Caspersen C Chen X Pollak S Chaney M Trinchese F Liu S Gunn-Moore F Lue LF Walker DG Kuppusamy P Zewier ZL Arancio O Stern D Yan SS Wu H ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's diseaseScience2004 304448452

    Not in our library10.1126/science.1091230

  99. 99.

    Meilandt WJ Yu GQ Chin J Roberson ED Palop JJ Wu T Scearce-Levie K Mucke L Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer's diseaseJ Neurosci2008 2850075017

    Not in our library10.1523/jneurosci.0590-08.2008

  100. 100.

    Simon AM Schiapparelli L Salazar-Colocho P Cuadrado-Tejedor M Escribano L Lopez de Maturana R Del Rio J Perez-Mediavilla A Frechilla D Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levelsNeurobiol Dis2009 33369378

    Not in our library10.1016/j.nbd.2008.11.005

  101. 101.

    Du H Guo L Zhang W Rydzewska M Yan S Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse modelNeurobiol Aging2011 32398406

    Not in our library10.1016/j.neurobiolaging.2009.03.003

  102. 102.

    Cisse M Sanchez PE Kim DH Ho K Yu GQ Mucke L Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic miceJ Neurosci2011 311042710431

    Not in our library10.1523/jneurosci.1459-11.2011

  103. 103.

    Palop JJ Jones B Kekonius L Chin J Yu GQ Raber J Masliah E Mucke L Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficitsProc Natl Acad Sci USA2003 10095729577

    Not in our library10.1073/pnas.1133381100

  104. 104.

    Fang F Chen X Huang T Lue LF Luddy JS Yan SS Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse modelBiochim Biophys Acta2012 1822286292

    Not in our library10.1016/j.bbadis.2011.10.004

  105. 105.

    Murakami K Yokoyama S Murata N Ozawa Y Irie K Shirasawa T Shimizu T Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer's-like phenotypes in miceBiochem Biophys Res Commun2011 4093439

    Not in our library10.1016/j.bbrc.2011.04.101

  106. 106.

    Escribano L Simon AM Perez-Mediavilla A Salazar-Colocho P Del Rio J Frechilla D Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse modelBiochem Biophys Res Commun2009 379406410

    Not in our library10.1016/j.bbrc.2008.12.071

  107. 107.

    Karl T Bhatia S Cheng D Kim WS Garner B Cognitive phenotyping of amyloid precursor protein transgenic J20 miceBehav Brain Res2012 228392397

    Not in our library10.1016/j.bbr.2011.12.021

  108. 108.

    Galvan V Gorostiza OF Banwait S Ataie M Logvinova AV Sitaraman S Carlson E Sagi SA Chevallier N Jin K Greenberg DA Bredesen DE Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664Proc Natl Acad Sci USA2006 10371307135

    Not in our library10.1073/pnas.0509695103

  109. 109.

    Xu F Grande AM Robinson JK Previti ML Vasek M Davis J Van Nostrand WE Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic miceNeuroscience2007 14698107

    Not in our library10.1016/j.neuroscience.2007.01.043

  110. 110.

    Fan R Xu F Previti ML Davis J Grande AM Robinson JK Van Nostrand WE Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloidJ Neurosci2007 2730573063

    Not in our library10.1523/jneurosci.4371-06.2007

  111. 111.

    Lalonde R Kim HD Fukuchi K Exploratory activity, anxiety, and motor coordination in bigenic APPswe + PS1/DeltaE9 miceNeurosci Lett2004 369156161

    Not in our library10.1016/j.neulet.2004.07.069

  112. 112.

    Cao D Lu H Lewis TL Li L Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer diseaseJ Biol Chem2007 2823627536282

    Not in our library10.1074/jbc.m703561200

  113. 113.

    Reiserer RS Harrison FE Syverud DC McDonald MP Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's diseaseGenes Brain Behav2007 65465

    Not in our library10.1111/j.1601-183x.2006.00221.x

  114. 114.

    Cramer PE Cirrito JR Wesson DW Lee CY Karlo JC Zinn AE Casali BT Restivo JL Goebel WD James MJ Brunden KR Wilson DA Landreth GE ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse modelsScience2012 33515031506

    Not in our library10.1126/science.1217697

  115. 115.

    Volianskis A Kostner R Molgaard M Hass S Jensen MS Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1deltaE9-deleted transgenic mice model of ss-amyloidosisNeurobiol Aging2010 3111731187

    Not in our library10.1016/j.neurobiolaging.2008.08.005

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    Ding Y Qiao A Wang Z Goodwin JS Lee ES Block ML Allsbrook M McDonald MP Fan GH Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse modelJ Neurosci2008 281162211634

    Not in our library10.1523/jneurosci.3153-08.2008

  117. 117.

    Bernardo A Harrison FE McCord M Zhao J Bruchey A Davies SS Jackson Roberts L Mathews PM Matsuoka Y Ariga T Yu RK Thompson R McDonald MP Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic miceNeurobiol Aging2009 3017771791

    Not in our library10.1016/j.neurobiolaging.2007.12.022

  118. 118.

    Ma T Du X Pick JE Sui G Brownlee M Klann E Glucagon-like peptide-1 cleavage product GLP-1(9-36) amide rescues synaptic plasticity and memory deficits in Alzheimer's disease model miceJ Neurosci2012 321370113708

    Not in our library10.1523/jneurosci.2107-12.2012

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    Lalonde R Kim HD Maxwell JA Fukuchi K Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co+PS1/DeltaE9 mice with amyloid plaquesNeurosci Lett2005 3908792

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    Zhang W Hao J Liu R Zhang Z Lei G Su C Miao J Li Z Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's diseaseBehav Brain Res2011 222342350

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    Knafo S Venero C Merino-Serrais P Fernaud-Espinosa I Gonzalez-Soriano J Ferrer I Santpere G DeFelipe J Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer's diseaseJ Pathol2009 2194151

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    O'Leary TP Brown RE Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer's diseaseBehav Brain Res2009 201120127

    Not in our library10.1016/j.bbr.2009.01.039

  123. 123.

    Holcomb L Gordon MN McGowan E Yu X Benkovic S Jantzen P Wright K Saad I Mueller R Morgan D Sanders S Zehr C O'Campo K Hardy J Prada CM Eckman C Younkin S Hsiao K Duff K Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenesNat Med1998 497100

    Not in our library10.1038/nm0198-097

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    Sadowski M Pankiewicz J Scholtzova H Ji Y Quartermain D Jensen CH Duff K Nixon RA Gruen RJ Wisniewski T Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 miceJ Neuropathol Exp Neurol2004 63418428

    Not in our library10.1093/jnen/63.5.418

  125. 125.

    Holcomb LA Gordon MN Jantzen P Hsiao K Duff K Morgan D Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid depositsBehav Genet1999 29177185

    Not in our library10.1023/a:1021691918517

  126. 126.
    Ferulic Acid Is a Nutraceutical β-Secretase Modulator That Improves Behavioral Impairment and Alzheimer-like Pathology in Transgenic Mice · 2013
    No notice
  127. 127.

    Gordon MN King DL Diamond DM Jantzen PT Boyett KV Hope CE Hatcher JM DiCarlo G Gottschall WP Morgan D Arendash GW Correlation between cognitive deficits and Aβ deposits in transgenic APP+PS1 miceNeurobiol Aging2001 22377385

    Not in our library10.1016/s0197-4580(00)00249-9

  128. 128.
    Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. · 2004
    No notice
  129. 129.

    Oakley H Cole SL Logan S Maus E Shao P Craft J Guillozet-Bongaarts A Ohno M Disterhoft J Van Eldik L Berry R Vassar R Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formationJ Neurosci2006 261012910140

    Not in our library10.1523/jneurosci.1202-06.2006

  130. 130.

    Jawhar S Trawicka A Jenneckens C Bayer TA Wirths O Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's diseaseNeurobiol Aging2012 33196.e129e140

    Not in our library10.1016/j.neurobiolaging.2010.05.027

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    Shukla V Zheng YL Mishra SK Amin ND Steiner J Grant P Kesavapany S Pant HC A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model miceFASEB J2013 27174186

    Not in our library10.1096/fj.12-217497

  132. 132.

    Ohno M Chang L Tseng W Oakley H Citron M Klein WL Vassar R Disterhoft JF Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1Eur J Neurosci2006 23251260

    Not in our library10.1111/j.1460-9568.2005.04551.x

  133. 133.

    Wirths O Erck C Martens H Harmeier A Geumann C Jawhar S Kumar S Multhaup G Walter J Ingelsson M Degerman-Gunnarsson M Kalimo H Huitinga I Lannfelt L Bayer TA Identification of low molecular weight pyroglutamate A[44] oligomers in Alzheimer disease: a novel tool for therapy and diagnosisJ Biol Chem2010 2854151741524

    Not in our library10.1074/jbc.m110.178707

  134. 134.

    Devi L Ohno M Genetic reductions of beta-site amyloid precursor protein-cleaving enzyme 1 and amyloid-beta ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model miceEur J Neurosci2010 31110118

    Not in our library10.1111/j.1460-9568.2009.07031.x

  135. 135.

    Devi L Ohno M Mitochondrial dysfunction and accumulation of the beta-secretase-cleaved C-terminal fragment of APP in Alzheimer's disease transgenic miceNeurobiol Dis2012 45417424

    Not in our library10.1016/j.nbd.2011.09.001

  136. 136.

    Tohda C Urano T Umezaki M Nemere I Kuboyama T Diosgenin is an exogenous activator of 1,25D(3)-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD miceSci Rep2012 2535

    Not in our library10.1038/srep00535

  137. 137.

    Urano T Tohda C Icariin improves memory impairment in Alzheimer's disease model mice (5xFAD) and attenuates amyloid beta-induced neurite atrophyPhytother Res2010 2416581663

    Not in our library10.1002/ptr.3183

  138. 138.

    Billings LM Oddo S Green KN McGaugh JL LaFerla FM Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic miceNeuron2005 45675688

    Not in our library10.1016/j.neuron.2005.01.040

  139. 139.

    Clinton LK Billings LM Green KN Caccamo A Ngo J Oddo S McGaugh JL LaFerla FM Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD miceNeurobiol Dis2007 287682

    Not in our library10.1016/j.nbd.2007.06.013

  140. 140.

    Gimenez-Llort L Blazquez G Canete T Johansson B Oddo S Tobena A LaFerla FM Fernandez-Teruel A Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloidNeurosci Biobehav Rev2007 31125147

    Not in our library10.1016/j.neubiorev.2006.07.007

  141. 141.

    Carroll JC Rosario ER Chang L Stanczyk FZ Oddo S LaFerla FM Pike CJ Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD miceJ Neurosci2007 271335713365

    Not in our library10.1523/jneurosci.2718-07.2007

  142. 142.

    Nelson RL Guo Z Halagappa VM Pearson M Gray AJ Matsuoka Y Brown M Martin B Iyun T Maudsley S Clark RF Mattson MP Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD miceExp Neurol2007 205166176

    Not in our library10.1016/j.expneurol.2007.01.037

  143. 143.

    Pietropaolo S Feldon J Yee BK Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer diseaseBehav Neurosci2008 122733747

    Not in our library10.1037/a0012520

  144. 144.

    Pietropaolo S Sun Y Li R Brana C Feldon J Yee BK Limited impact of social isolation on Alzheimer-like symptoms in a triple transgenic mouse modelBehav Neurosci2009 123181195

    Not in our library10.1037/a0013607

  145. 145.

    Sterniczuk R Antle MC Laferla FM Dyck RH Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 2. Behavioral and cognitive changesBrain Res2010 1348149155

    Not in our library10.1016/j.brainres.2010.06.011

  146. 146.
    DHA Improves Cognition and Prevents Dysfunction of Entorhinal Cortex Neurons in 3xTg-AD Mice · 2011
    No notice
  147. 147.

    Filali M Lalonde R Theriault P Julien C Calon F Planel E Cognitive and non-cognitive behaviors in the triple transgenic mouse model of Alzheimer's disease expressing mutated APP, PS1, and Mapt (3xTg-AD)Behav Brain Res2012 234334342

    Not in our library10.1016/j.bbr.2012.07.004

  148. 148.

    Stewart S Cacucci F Lever C Which memory task for my mouse? A systematic review of spatial memory performance in the Tg2576 Alzheimer's mouse modelJ Alzheimers Dis2011 26105126

    Not in our library10.3233/jad-2011-101827

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    Gulinello M Gertner M Mendoza G Schoenfeld BP Oddo S LaFerla F Choi CH McBride SM Faber DS Validation of a 2-day water maze protocol in miceBehav Brain Res2009 196220227

    Not in our library10.1016/j.bbr.2008.09.002

  150. 150.

    Halagappa VK Guo Z Pearson M Matsuoka Y Cutler RG Laferla FM Mattson MP Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's diseaseNeurobiol Dis2007 26212220

    Not in our library10.1016/j.nbd.2006.12.019

  151. 151.

    Games D Adams D Alessandrini R Barbour R Berthelette P Blackwell C Carr T Clemens J Donaldson T Gillespie F Guido T Hagopian S Johnson-Wood K Khan K Lee M Leibowitz P Lieberburg I Little S Masliah E McConlogue L Montoya-Zavala M Mucke L Paganini L Penniman E Power M Schenk D Seubert P Snyder B Soriano F Tan H Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor proteinNature1995 373523527

    Not in our library10.1038/373523a0

  152. 152.

    Sturchler-Pierrat C Abramowski D Duke M Wiederhold KH Mistl C Rothacher S Ledermann B Burki K Frey P Paganetti PA Waridel C Calhoun ME Jucker M Probst A Staufenbiel M Sommer B Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathologyProc Natl Acad Sci USA1997 941328713292

    Not in our library10.1073/pnas.94.24.13287

  153. 153.

    Mucke L Masliah E Yu GQ Mallory M Rockenstein EM Tatsuno G Hu K Kholodenko D Johnson-Wood K McConlogue L High-level neuronal expression of aβ 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formationJ Neurosci2000 2040504058

    Not in our library10.1523/jneurosci.20-11-04050.2000

  154. 154.

    Davis J Xu F Deane R Romanov G Previti ML Zeigler K Zlokovic BV Van Nostrand WE Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursorJ Biol Chem2004 2792029620306

    Not in our library10.1074/jbc.m312946200

  155. 155.

    Jankowsky JL Slunt HH Ratovitski T Jenkins NA Copeland NG Borchelt DR Co-expression of multiple transgenes in mouse CNS: a comparison of strategiesBiomol Eng2001 17157165

    Not in our library10.1016/s1389-0344(01)00067-3

  156. 156.

    Oddo S Caccamo A Shepherd JD Murphy MP Golde TE Kayed R Metherate R Mattson MP Akbari Y LaFerla FM Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunctionNeuron2003 39409421

    Not in our library10.1016/s0896-6273(03)00434-3

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