APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.     

Structural brain variation,age, and response time

Response time (RT) generally slows with aging, but the contribution of structural brain changes to this slowing is unknown. We used voxel-based morphometry (VBM) to determine gray matter (GM) and white matter (WM) brain volumes in 9 middle-aged adults (38–58 years old) and 9 seniors (66–82 years old). We correlated brain volumes with RT assessed in both a simple visual stimulus-response task and a visual continuous recognition memory task. No GM correlations with simple RT were significant; there was one WM correlation in the right fusiform gyrus. In the memory task, faster RT was correlated (p<.05, corrected) with less GM in the globus pallidus, the parahippocampus, and the thalamus for both groups. Several Brodmann areas (BA) differed between the groups such that in each area, less GM was correlated with slower RTs in the middle-aged group but with faster RTs in the senior group (BAs 19, 37, 46, 9, 8, 6, 13, 10, 41, and 7). The results suggest that individual differences in specific brain structure volumes should be considered as potential moderating factors in cognitive brain imaging studies.     

An automated version of the operation span task

We present an easy-to-administer and automated version of a popular working memory (WM) capacity task (operation span; Ospan) that is mouse driven, scores itself, and requires little intervention on the part of the experimenter. It is shown that this version of Ospan correlates well with other measures of WM capacity and has both good internal consistency (alpha=.78) and test-retest reliability (.83). In addition, the automated version of Ospan (Aospan) was shown to load on the same factor as two other WM measures. This WM capacity factor correlated with a factor composed of fluid abilities measures. The utility of the Aospan was further demonstrated by analyzing response times (RTs) that indicated that RT measures obtained in the task accounted for additional variance in predicting fluid abilities. Our results suggest that Aospan is a reliable and valid indicator of WM capacity that can be applied to a wide array of research domains.     

The functional significance of theta and upper alpha oscillations

Recent findings are reviewed indicating that upper alpha oscillations - when analyzed with appropriate time/ frequency resolution - show a similar physiological reactivity as theta in working memory tasks. Comparable to theta, a load dependent increase in power can be observed during retention and increased evoked activity during retrieval. During retrieval attempts theta behaves like a traveling wave spreading from anterior to posterior sites. During actual retrieval, however, evoked upper alpha becomes transiently nested in theta. We suggest that theta reflects working memory functions whereas upper alpha may be important for the reactivation of long-term memory codes in short-term memory.