The relationship between abeta and memory in tg2576 mouse model of alzheimers disease

Studies of the relationship between memory and Aß in transgenic mice . Memory in Tg mice has been measured by several groups. Various and A{beta} Pathology in a Transgenic Mouse Model of Alzheimer's Disease J. Pharmacol. The relationship between Abeta and memory in the Tg mouse model of Alzheimer's disease. J Neurosci. ; – pmid. Behavioral tests discussed include spatial memory tests (Morris water maze, Mouse models of AD and the behavioral tasks used in conjunction with those in males in transgenic Tg mouse model of Alzheimer's disease. . Alzheimer's disease and the basal forebrain cholinergic system: relations to beta- amyloid.

In all three studies, probe trials were performed only after extensive training that probably saturated learning and reduced the sensitivity of the test. Reductions in LTP recorded in vitro were present in old to month-old but not young 2- to 8-month-old mice. Taken together, these results suggest increased vulnerability of Tg hippocampal slices to NMDA-mediated excitotoxic damage with age and that in vitro LTP in some circumstances may reflect the susceptibility of Tg hippocampal tissue to the trauma of slice preparation, rather than long-lasting synaptic plasticity.

The vulnerability of the tissue appears to increase with worsening cognitive function, accounting for the correlation between working memory and LTP. However, this would not explain the diminution of LTP recorded in vivo in the dentate gyrus of to month-old Tg mice Chapman et al.

There are several possible reasons for the disparity between in vitro and in vivo LTP results in Tg, including the presence of a diffusible factor disrupting cognition that might be diluted in slice preparations, the involvement of modulating afferent pathways to the hippocampus that would be severed in slice preparations, or the contributions of synaptically mediated cerebrovascular responses that would make no contributions in vitro.

Two correlative studies in PDAPP mice and mice bigenic for the mutant presenilin-1 and Tg transgenes showed significant negative correlations between memory and amyloid load Chen et al. This is discussed more thoroughly below.

The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease.

Using a working-memory version of the Morris water maze, deterioration in the age-dependent component of working memory in PDAPP mice was first detected at 13—15 mo and not at 6—9 mo Chen et al.

The earliest reported deficits in radial arm water maze performance were in month-old Tg mice and no deficits were found at 11 mo Morgan et al. It is more likely that the dynamic ranges of the currently used paradigms to measure spatial working memory in the water maze are tuned to reveal more severe age-dependent deficits occurring in older Tg and PDAPP mice but may miss the more subtle abnormalities developing in younger mice.

This break down would not have been evident in previous studies examining only one age range Chen et al. Taken along with the studies by Ashe and colleagues Westerman et al. Semantic memory deficits are the next to develop Tuokko et al. As MCI progresses, deficits in verbal recall Kryscio et al. As the patient transitions into AD, all cognitive domains become affected. Consistently, the earliest observable impairments are in spatial working memory Webster et al.

These impairments are generally followed temporally by impairments in associative learning and reference memory, as assessed by maze alternation Lalonde et al. Deficits in recognition memory usually present later in the spectrum of cognitive impairment than deficits in other domains Eriksen and Janus, ; Hall and Roberson, ; Webster et al. Some of the earliest neuropathological changes in AD are in the hippocampus and entorhinal cortex, followed by changes in the medial temporal lobe.

Consistent with this progression of pathology, the earliest detectable deficits in cognition are seen in medial temporal lobe-dependent episodic memory Bondi et al.

Learning and Memory in Transgenic Mice Modeling Alzheimer's Disease

These early deficits in episodic memory are followed closely by deficits in semantic memory, and both are developed before other deficits in cognitive domains such as attention, visuospatial memory, or executive function Bondi et al.

This suggests that cognitive functions such as episodic and semantic memory that depend heavily on the neural circuitry of the medial and lateral temporal lobes may be impaired earlier than cognitive abilities that depend on the circuitry of other brain regions. Further support for this idea comes from the time course of the frontal lobe dependent executive function deficits observed in patients.

Slight deficits in executive functioning are first detectable near the end of the preclinical phase of AD but after the observed deficits in episodic and semantic memory Storandt et al.

As the patient moves from the preclinical phase of AD into MCI, more cognitive domains begin to be affected. Most studies of MCI patients show consistent impairments in verbal recall Larrieu et al.

Once the AD patient progresses past MCI and into dementia, general cognition continues to decline with deficits appearing in all respective cognitive domains Huff et al. The importance of neuropsychological testing cannot be overstated, as it is the only measure that provides information about a patient's current cognitive status and remains the most reliable means to clinically diagnose probable AD.

Neuropsychological testing provides information on both general cognitive status and specific information on different cognitive domains affected in AD. Composite scores encompassing multiple neuropsychological tests are often used and can provide some of the most reliable assessments of global cognitive status relating to AD as well as serving as efficacy outcome measures in clinical trials Bernick et al.

Ideally, preclinical rodent cognitive testing would assess identical cognitive domains to those examined through neuropsychological testing in human AD. Indeed, many rodent behavioral tasks have been specifically designed with this in mind, and while each task varies with respect to face, construct, and predictive validity, they all attempt to model different aspects of the cognition disrupted in AD and targeted by the human neuropsychological assessments listed in the previous section.

Some cognitive domains disrupted in AD have been extensively modeled reference memory, working memory and executive functionsome less so attentionand some nearly not at all episodic memory. Reference memory, while not used clinically to describe human cognition, refers to learned knowledge for an aspect of a task that remains constant throughout the behavioral task and most closely correlates to human semantic memory.

Working memory refers to a mental processing system used to hold transitory information for a limited time where it can be manipulated and operated on and used to guide behavior. Recognition memory refers to the ability to recognize previously encountered events, objects, or individuals and is classified as part of long-term declarative memory. Other cognitive domains impaired in human AD such as those involving language i.

Table 2 provides a short description of various behavioral tasks used to assess AD-like cognitive deficits in mice, and summarizes the respective cognitive domains measured by each task. Commonly used mouse behavioral tasks. Modeling Working Memory Working memory is perhaps one of the most well modeled aspects of the memory deficits in AD.

Clinically, many of the neuropsychological tests that assess working memory rely heavily on the use of verbal tasks Kaplan et al. Instead, spatial based working memory tasks are heavily employed in murine working memory testing and likely are more depictive of the visuospatial working memory tasks used clinically Benton, ; Benedict and Groninger, The most widely used paradigms for working memory in mice are maze type tasks which require spatial working memory to solve.

The earliest variants of these are the T-maze and Y-maze alternation tasks, which are relatively simple tests consisting of three arms with a single intersection. These tasks rely on the natural exploratory behavior tendency to choose an alternative arm over an arm which has been previously explored of rodents and are considered the most rudimentary tasks to assess spatial working memory Dudchenko, A more complex maze type task used to test murine spatial working memory is that of the Radial Arm Maze RAMconsisting of several arms usually 6—8 radiating outwards from a central platform Olton and Samuelson, ; Olton et al.

In the RAM, the animal is started in the center area and then some of the arms or all of the arms can be baited with a food reward.

Depending on the baiting paradigm, unimpaired rats and mice will quickly learn where the food reward is and which arms have previously been visited, and will avoid re-entering a previously entered arm. The MWM consists of a large open pool with a hidden submerged escape platform located somewhere within the pool.

Animals must learn where the platform is, remember the platform's location, and then use spatial cues on subsequent trials to navigate back to the hidden platform.

It is important to note that while many of the previously described behavioral tasks are considered tasks of working memory they can also be modified to test reference memory depending on the testing protocol used.

Similarly, not all models of murine working memory are spatial working memory tasks. In these non-spatial working memory tasks the animal is required to remember a stimulus over a delay period that is paired with a particular type of response generally a lever press or a nose poke and a correct response is rewarded. In many of the non-spatial operant working memory tasks each animal can perform many trials per day and thus can serve as its own control.

This lends itself nicely to pharmacological based studies assessing potential therapeutic compounds for the treatment of the cognitive deficits seen in AD Buccafusco et al. Modeling Executive Function Executive function refers to a broad range of higher cognitive processes such as: The current mouse models of executive function most closely replicate the human aspects of cognitive flexibility and response inhibition in executive function.

the relationship between abeta and memory in tg2576 mouse model of alzheimers disease

Attentional set-shifting tasks are one of the main behavioral tasks used to assess executive function in the mouse. In many ways, set-shifting tasks are similar to the Wisconsin Card Sorting Task in that they form the gold standard for assessing executive function Drewe, ; Robinson et al. In both the Wisconsin Card Sorting Task in humans and set-shifting tasks in mice, the dorsolateral and orbital prefrontal cortex is critical for successful performance Weinberger et al.

(PDF) The Relationship between A?? and Memory in the Tg Mouse Model of Alzheimer's Disease

In the most common version of the murine set-shifting task, mice are required to select a bowl in which to dig for a food reward. Bowls can be discriminated from each other according to different stimulus dimensions such as texture and odor.

Successful completion of the task requires the animal to shift between stimuli dimensions to successfully retrieve the food reward.

The ability to extract knowledge from different stimuli dimensions suggests that the mouse is capable of using at least some aspects of higher-order cognitive functions seen in human executive functioning Chudasama, Numerous different transgenic mouse models of AD have shown deficits in set-shifting tasks Zhuo et al.

Reversal learning is another way that aspects of executive function are modeled in the mouse. While less complex than attentional set shifting, reversal learning does require both cognitive flexibility and impulse control, thus tapping into components of human executive function Chudasama, ; Stopford et al. There are many different variations of reversal learning tasks in mouse behavior, but they all work on the same principle.

The animal first learns that a particular response to a stimulus will be rewarded, while a response to a different stimulus will be unrewarded. Then the stimulus-reward is switched so that the previously unrewarded stimulus becomes the rewarded stimulus.

The animal must learn to reverse responses in order to receive the reward. Wild type control mice are able to quickly adjust their response in order to obtain the reward. However, animals with prefrontal cortex lesions display profound deficits in reversal learning Chudasama, ; Izquierdo and Jentsch, Similarly, many different AD mouse models have shown impairment in reversal learning Angelo et al.

Another aspect of executive function that is modeled in mice is response inhibition. Response inhibition is required for the appropriate control of an individual's behavioral actions in response to a stimulus Robbins, ; Humby et al. The five choice serial reaction time task 5-CSRTT is a behavioral task that measures the response inhibition component of executive function 5-CSRTT is also used to model aspects of attention, see below section in mice Robbins, ; Bari et al.

Modeling Attention Several behavioral tasks have been developed for modeling attention in mice that provide reliable measures comparable to the neuropsychological assessments used in AD. This task employs an operant box with nose poke holes on the front wall of the chamber. Animals are trained to respond to brief flashes of light corresponding to five different spatial locations on this front side of the chamber and correct responses are rewarded with a food pellet released to a feeder box at the rear of the chamber.

Touchscreen versions of this task are also available in which the nose poke holes and stimulus lights are replaced with an LCD screen Romberg et al.

The relationship between Abeta and memory in the Tg mouse model of Alzheimer's disease.

For both standard and touchscreen versions of the task, multiple trials are run each day and both the duration of the stimulus itself or the interval between the stimulus and response can be manipulated to increase the attention demands placed on the animal. Sustained attention is measured by examining when the animal responds to a different incorrect hole than where the stimulus light appeared called errors of commissionfails to respond within the allotted time to the stimulus errors of omissionand the speed with which the animal responds reaction time.

Aspects of selective attention can also be modeled with the 5-CSRTT by introducing brief bursts of white noise that the animal must ignore while still detecting the visual stimulus as it is presented Robbins, ; Bari et al.

Both tasks require subjects mouse and human respectively to utilize sustained attention divided among multiple spatial locations across which a large number of trials and errors of commission, omission, and reaction time are scored.

the relationship between abeta and memory in tg2576 mouse model of alzheimers disease

In this task, the subjects are asked to respond to signal and non-signal events across numerous trials, and scores of hits, misses, rejections, and false alarms are recorded.

However, the homology between mouse and human versions of these tasks is far from perfect, and caution should be used when drawing conclusions from the rodent 5-CSRTT and applying them to human attention Young et al. Modeling Episodic Memory Episodic memory refers to the ability to encode and recall personal past events and experiences.

Modeling AD-related deficits in episodic memory in mice is a less well-explored area than that of other aspects of working memory, executive function, or attention.

the relationship between abeta and memory in tg2576 mouse model of alzheimers disease

Historically, episodic memory was thought to be unique to humans Tulving and Markowitsch, However, work over the past few decades on episodic-like memory across a number of animal species has suggested otherwise, and several mouse behavioral tasks designed at assessing episodic-like memory have been developed Clayton and Dickinson, ; Clayton et al.

This task is an adaptation of the NOR task. While the NOR task itself is too simplistic a task to be considered a true episodic memory task rather it is considered a task of recognition memorythe WWWhich task is able to model episodic-like memory. In the WWWhich task, the animal must integrate the location of a particular object with specific contextual cues to form an episodic-like memory Davis et al.

Several studies employing the WWWhich task have observed performance deficits related to the aging process and to AD disease state in several transgenic mouse lines Davis et al.

Alzheimer's and the Brain

While the WWWhich task models episodic memory in the mouse, it is not very comparable to any of the episodic memory tasks commonly used in neuropsychological testing for AD. This is largely because the human tasks rely on language as a foundational construct for assessment.

Obviously, there exists no such component in the WWWhich task for mice. Therefore, caution should be used when attempting to correlate any preclinical finding concerning episodic memory in mice to that of human cognition.

Summary of Mouse Behavioral Tests All of the rodent behavioral tasks discussed in this section have been specifically developed to assess deficits in cognitive domains related to what is seen in human AD. Just as multiple neuropsychological tests assessing different cognitive domains are often used clinically to provide a global cognitive profile, so multiple behavioral tasks assessing different cognitive domains should ideally be used when characterizing the profile of AD-related cognitive impairment in a particular mouse model of AD.

Although no one animal model fully replicates the progression of cognitive impairments seen in the human disease, AD mouse models have been invaluable in advancing our knowledge of the disease.

It should be noted that most of the AD mouse models are representative of the familial form of AD FAD which accounts for only a small percentage of the total AD cases each year Campion et al.

the relationship between abeta and memory in tg2576 mouse model of alzheimers disease