Transgenic Mouse Models as Tools for Understanding How Increased Cognitive and Physical Stimulation Can Improve Cognition in Alzheimer’s Disease

Abstract

Cognitive decline appears as a core feature of dementia, of which the most prevalent form, Alzheimer’s disease (AD) affects more than 45 million people worldwide. There is no cure, and therapeutic options remain limited. A number of modifiable lifestyle factors have been identified that contribute to cognitive decline in dementia. Sedentary lifestyle has emerged as a major modifier and accordingly, boosting mental and physical activity may represent a method to prevent decline in dementia. Beneficial effects of increased physical activity on cognition have been reported in healthy adults, showing potential to harness exercise and cognitive stimulation as a therapy in dementia. ‘Brain training’ (cognitive stimulation) has also been investigated as an intervention protecting against cognitive decline with normal aging. Consequently, the utility of exercise regimes and/or cognitive stimulation to improve cognition in dementia in clinical populations has been a major area of study. However, these therapies are in their infancy and efficacy is unclear. Investigations utilising animal models, where dose and timing of treatment can be tightly controlled, have provided many mechanistic insights. Genetically engineered mouse models are powerful tools to investigate mechanisms underlying cognitive decline, and also how environmental manipulations can alter both cognitive outcomes and pathology. A myriad of effects following physical activity and housing in enriched environments have been reported in transgenic mice expressing Alzheimer’s disease-associated mutations. In this review, we comprehensively evaluate all studies applying environmental enrichment and/or increased physical exercise to transgenic mouse models of Alzheimer’s disease. It is unclear whether interventions must be applied before first onset of cognitive deficits to be effective. In order to determine the importance of timing of interventions, we specifically scrutinised studies exposing transgenic mice to exercise and environmental enrichment before and after first report of cognitive impairment. We discuss the strengths and weaknesses of these preclinical studies and suggest approaches for enhancing rigor and using mechanistic insights to inform future therapeutic interventions.

Voluntary running does not increase capillary blood flow but promotes neurogenesis and short-term memory in the APP/PS1 mouse model of Alzheimer’s disease

“…The trends toward improved cognitive function (Fig 2), the clear increase in neurogenesis, as well as the lack of a notable impact on brain inflammation and amyloid deposition (Fig. 3 and 4) that we observed are consistent with previous studies of the impact of exercise on mouse models of AD [72]. We next sought to determine if these exercise-mediated changes were correlated with an increase in brain blood flow, perhaps linked to a decrease in the incidence of non-flowing capillaries.…”

“…We found performance in the object replacement task in 12-month-old APP/PS1 mice was markedly improved by three months of voluntary wheel running, as compared to sedentary controls, while no improvements were detected in the novel object recognition task and Y-maze tasks. This exercise-related improvement in performance on some memory-related tasks but not on others is consistent with similarly mixed impacts of exercise in previous studies of memory function in mouse models of AD [72] and in AD patients [78]. While a variety of brain regions are likely involved in each of these memory tasks, it has been shown that memory of an object’ s spatial location (evaluated with object replacement task) is highly dependent on hippocampal regions, while memory of an object’ s intrinsic characteristics (evaluated with novel object task) also involves significant contributions from other brain regions, such as the temporal lobe [79-81].…”

Early Cognitive Training Rescues Remote Spatial Memory but Reduces Cognitive Flexibility in Alzheimer’s Disease Mice

“…Multiple studies show that lifestyle interventions such as environmental enrichment and exercise rescue spatial learning and memory in WM task [38,39]. However, some studies have also reported that exercise does not improve the spatial learning and memory in AD mice [40]. Rather, environmental enrichment improves the WM performance of AD mice [41].…”

“…Physical exercise intervention shows an improvement or rescue of cognitive dysfunction in AD mouse models [40] with one exception [41]. Measures such as active lifestyle, education, or physical exercise help to rescue the cognitive function in elderly [40]. Similarly, earlier report from Nun Study points possibility of the positive association between the genetic risk factor such as 4 allele of apolipoprotein E (APOE 4) and dementia [51].…”

“…Physical exercise intervention shows an improvement or rescue of cognitive dysfunction in AD mouse models [40] with one exception [41]. Measures such as active lifestyle, education, or physical exercise help to rescue the cognitive function in elderly [40].…”