Benjamin F. Timson

Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer’s disease

We examined the effects of voluntary (16 weeks of wheel running) and forced (16 weeks of treadmill running) exercise on memory-related behavior, hippocampal volume, thioflavine-stained plaque number, and soluble Abeta levels in brain tissue in the Tg2576 mouse model of Alzheimers disease (AD). Voluntary running animals spent more time investigating a novel object in a recognition memory paradigm than all other groups. Also, voluntary running animals showed fewer thioflavine S stained plaques than all other groups, whereas forced running animals showed an intermediate number of plaques between voluntary running and sedentary animals. Both voluntary and forced running animals had larger hippocampal volumes than sedentary animals. However, levels of soluble Abeta-40 or Abeta-42 did not significantly differ among groups. The results indicate that voluntary exercise may be superior to forced exercise for reducing certain aspects of AD-like deficits - i.e., plaque deposition and memory impairment, in a mouse model of AD.

A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer's disease

Physical activity has long been hypothesized to influence the risk and pathology of Alzheimers disease. However, the amount of physical activity necessary for these benefits is unclear. We examined the effects of three months of low and high intensity exercise training on soluble Aβ40 and Aβ42 levels in extracellular enriched fractions from the cortex and hippocampus of young Tg2576 mice. Low (LOW) and high (HI) intensity exercise training animals ran at speeds of 15m/min on a level treadmill and 32 m/min at a 10% grade, respectively for 60 min per day, five days per week, from three to six months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. Soleus muscle citrate synthase activity increased by 39% in the LOW group relative to SED, and by 71% in the HI group relative to LOW, indicating an exercise training effect in these mice. Soluble Aβ40 concentrations decreased significantly in an exercise training dose-dependent manner in the cortex. In the hippocampus, concentrations were decreased significantly in the HI group relative to LOW and SED. Soluble Aβ42 levels also decreased significantly in an exercise training dose-dependent manner in both the cortex and hippocampus. Five proteins involved in Aβ clearance (neprilysin, IDE, MMP9, LRP1 and HSP70) were elevated by exercise training with its intensity playing a role in each case. Our data demonstrate that exercise training reduces extracellular soluble Aβ in the brains of Tg2576 mice in a dose-dependent manner through an up-regulation of Aβ clearance.

Interactions between stress and physical activity on Alzheimer's disease pathology

Physical activity and stress are both environmental modifiers of Alzheimers disease (AD) risk. Animal studies of physical activity in AD models have largely reported positive results, however benefits are not always observed in either cognitive or pathological outcomes and inconsistencies among findings remain. Studies using forced exercise may increase stress and mitigate some of the benefit of physical activity in AD models, while voluntary exercise regimens may not achieve optimal intensity to provide robust benefit. We evaluated the findings of studies of voluntary and forced exercise regimens in AD mouse models to determine the influence of stress, or the intensity of exercise needed to outweigh the negative effects of stress on AD measures. In addition, we show that chronic physical activity in a mouse model of AD can prevent the effects of acute restraint stress on Aβ levels in the hippocampus. Stress and physical activity have many overlapping and divergent effects on the body and some of the possible mechanisms through which physical activity may protect against stress-induced risk factors for AD are discussed. While the physiological effects of acute stress and acute exercise overlap, chronic effects of physical activity appear to directly oppose the effects of chronic stress on risk factors for AD. Further study is needed to identify optimal parameters for intensity, duration and frequency of physical activity to counterbalance effects of stress on the development and progression of AD.

Effect of treadmill running on soluble beta-amyloid concentrations in brains of young Tg2576 mice

Background: Alzheimer’s disease and Parkinson’s disease are the two most common neurodegenerative diseases, which are characterized by amyloid-beta (A b) plaques and alpha-synuclein (a-syn) rich Lewy bodies, respectively. An overlap of these two pathologies is found in patients with Lewy Body Dementia (LBD). Postmortem brains of LBD patients display significant synuclein accumulation in dystrophic neurites decorating A b plaques. Furthermore, in vitro studies report co-aggregation of Ab and a-syn, yet the precise role of a-syn in amyloid plaque formation remains elusive. Methods: In order to investigate a putative interaction of a-syn with amyloid plaque formation in vivo, we crossed APPPS1 with (Thy1)-[A30P]a-syn transgenic mice. Immunhistochemical and biochemical analysis revealed that a-syn affects amyloid plaque formation in vivo, whereas overall APP levels remain unaffected by the additional a-syn expression. Results: To further study the effect of a-syn on A b deposition, we performed cerebral stereotactic injections of 1) brain homogenate from aged APPPS1 transgenic mice into APPPS1x[A30P]a-syn transgenic mice and 2) a mixed preparation of brain homogenates from APPPS1 and (Thy1)-[A30P]a-syn transgenic mice into APPPS1 transgenic mice. We observed reduced seeding of Ab plaques under both experimental conditions, implying an inhibitory effect of a-syn on Ab plaque formation. Conclusions: In summary, our data suggest that a-syn plays an important role in Ab deposition. This work deepens our understanding of the complex pathophysiology of LBD and many other, related neurodegenerative diseases.

Altered running economy in the Tg2576 mouse model of Alzheimer's disease

pressing the responder transgene are maintained on a FVB/NCrl strain. All bigenic progeny will be on a strain background that is 50% FVB and 50% 129S. To address the effect of strain background on pathology progression in this model, we have created a B6/rTg4510 mouse line in which the same responder mice on the FVB/NCrl background are now bred with C57BL/6J mice expressing the activator transgene to create bigenic offspring that are now 50% FVB and 50% B6. To determine if the introduction of the B6 background would delay the pathological progression, we have harvested cohorts of B6/rTg4510 mice at 5.5M, 6.5M and 10.5M of age. Tau pathology will be assessed by biochemical and immunohistochemical analysis. To assess effects on cognition, we have also behaviorally tested the 6.5M and 10.5M cohorts with the Morris water maze. Results: Initial biochemical analysis of soluble and sarkosyl-insoluble tau by western blot analysis shows that B6/rTg4510 mice do not have a delay in the progression of tau pathology as compared to the original rTg4510 line. Interestingly though, the B6/rTg4510 females have a trending increase in 64kd tau as compared to males of their own line and males and females of the original rTg4510 line. Further analysis is ongoing to determine the nature and significance of the initial differences detected. Behavioral data supports the initial biochemical analysis in that both lines are cognitively impaired and do not significantly differ in this impairment from one another. Immunohistochemical analysis is ongoing and will be complete by March 15. At the time of the conference, full behavioral, biochemical and immunohistochemical analysis will be presented. Conclusions: Unlike the previous report of a delay in tauopathy progression in the JNPL3 transgenic mouse line with the introduction of the C57BL/ 6J background strain, we do not observe the same changes in the rTg4510 mouse model as assessed by behavior and preliminary biochemical analysis. Immunohistochemical analysis is ongoing and a full assessment will be presented.