Exercise Training Results in Lower Amyloid Plaque Load and Greater Cognitive Function in an Intensity Dependent Manner in the Tg2576 Mouse Model of Alzheimer's Disease.

Three months of exercise training (ET) decreases soluble Aß40 and Aß42 levels in an intensity dependent manner early in life in Tg2576 mice (Moore et al., 2016). Here, we examined the effects of 12 months of low- and high- intensity exercise training on cognitive function and amyloid plaque load in the cortex and hippocampus of 15-month-old Tg2576 mice. Low- (LOW) and high- (HI) intensity ET animals ran at speeds of 15 m/min on a level treadmill and 32 m/min at a 10% grade, respectively, for 60 min/day, five days/week, from 3 to 15 months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. ET mice demonstrated a significantly lower amyloid plaque load in the cortex and hippocampus that was intensity dependent. Improvement in cognitive function, assessed by Morris Water Maze and Novel Object Recognition tests, was greater in the HI group compared to the LOW and SED groups. LOW mice performed better in the initial latency to the platform location during the probe trial of the Morris Water Maze (MWM) test than SED, but not in any other aspect of MWM or the Novel Object Recognition test. The results of this study indicate that exercise training decreases amyloid plaque load in an intensity dependent manner and that high-intensity exercise training improves cognitive function relative to SED mice, but the intensity of the LOW group was below the threshold to demonstrate robust improvement in cognitive function in Tg2576 mice.

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

Physical activity and stress are both environmental modifiers of Alzheimer's 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 Aß 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.

A spectrum of exercise training reduces soluble Aß 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 Alzheimer's 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 Aß40 and Aß42 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 Aß40 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 Aß42 levels also decreased significantly in an exercise training dose-dependent manner in both the cortex and hippocampus. Five proteins involved in Aß 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 Aß in the brains of Tg2576 mice in a dose-dependent manner through an up-regulation of Aß clearance.

Characterization of biomolecular nanoconjugates by high-throughput delivery and spectroscopic difference.

AIM: Nanoparticle conjugates have the potential for delivering siRNA, splice-shifting oligomers or nucleic acid vaccines, and can be applicable to anticancer therapeutics. This article compares tripartite conjugates with gold nanoparticles or synthetic methoxypoly(ethylene glycol)-block-polyamidoamine dendrimers. MATERIALS & METHODS: Interactions with model liposomes of a 1:1 molar ratio of tripalmitin:cholesterol or phospholipid:cholesterol were investigated by high-throughput absorbance, as well as fluorescence difference and cellular luminescence assays. RESULTS: Spectral differences and dynamic light-scattering spectroscopy shifts demonstrated the interaction of conjugates with liposomes. Biological activity was demonstrated by upregulation of gene expression via splice-shifting oligomers, delivery of anti-B-Raf siRNA in cultured human cancer cells or tuberculosis antigen 85B plasmid expression vector in a coculture model of antigen presentation. CONCLUSION: The data suggests that gold nanoparticles and methoxypoly(ethylene glycol)-block-polyamidoamine dendrimer nanoconjugates may have potential for binding, stabilization and delivery of splice-shifting oligomers, siRNA and nucleic acid vaccines for preclinical trials.

Exercise training post-MI favorably modifies heart extracellular matrix in the rat.

PURPOSE: In order to assess the effect of daily exercise on extracellular matrix remodeling in the heart after myocardial infarction (MI), we measured collagen concentration (%COL) and nonreducible collagen cross-linking (hydroxylysylpyridinoline, HP) in the right ventricle (RV), and regionally within the infarcted (INF) and viable left ventricular free wall (LVF) and septum (LVS), using a rodent MI training model. METHODS: Infarcts (19%-24% of LV) were surgically induced in adult rats that were assigned to either trained (MI-TR) or sedentary (MI-SED) groups and compared to sham-surgery sedentary controls (SHAM). RESULTS: In LVF, 10 wk of treadmill running had no effect on the increase (P < 0.001) in %COL seen with MI (MI-SED = 7.14% ± 0.15%, MI-TR = 7.61% ± 0.19%, SHAM = 3.55% ± 0.19%). However, it normalized the increase (P < 0.05) in HP cross-linking (MI-SED = 0.43 ± 0.02, MI-TR = 0.27 ± 0.03, SHAM = 0.30 ± 0.04 mol HP·mol(-1) collagen). The INF scar in MI-SED rats showed a sevenfold increase in %COL (P < 0.001) compared to SHAM LVF myocardium, an increase that was attenuated by training (MI-SED = 26% ± 1% vs MI-TR = 21% ± 2%; P < 0.05). However, training had no effect on MI-induced increases in cross-linking in the INF scar (1.01 ± 0.22 vs 0.84 ± 0.14 mol HP·mol(-1) collagen). In LVS, although a small but significant increase in %COL was seen in both MI groups, HP cross-linking was unaltered compared to SHAM rats. Training also normalized the increase observed in cross-linking in RV after MI. CONCLUSIONS: Because increased HP cross-linking in the heart is associated with decreased chamber compliance, these findings may help to explain the improved heart function seen after daily exercise in cardiac rehabilitation patients.

Impact of interdisciplinary learning on critical thinking using case study method in allied health care graduate students.

It remains unclear which classroom experiences, if any, foster critical think ability. We measured the effectiveness of interdisciplinary, case-based learning on the critical-thinking ability of graduate students enrolled in allied health care programs. We designed a voluntary classroom experience to examine the effectiveness of case studies used in an interdisciplinary setting to increase critical-thinking ability. Two groups of students were measured for their critical thinking ability using an online assessment both before and after their respective classroom experiences. One group of 14 graduate students from 4 different allied health care programs (interdisciplinary, ID) discussed complex interdisciplinary case studies and answered multiple-choice type questions formed around the cases. The second group was composed of graduate students (n = 28) from a single disciple enrolled in a clinical anatomy course (discipline specific, DS). They discussed complex case studies specific to their discipline and answered multiple-choice questions formed around the cases. There was no overall change in critical-thinking scores from the pre- to post-test in either group (delta scores: ID 1.5 ± 5.3, DS -1.7 ± 5.7). However, ID students scoring below the median on the pretest improved significantly (paired t-test, pre 50.7 ± 3.8, post 54.2 ± 1.7, p = 0.02). The interdisciplinary learning experience improved critical-thinking ability in students with the least proficiency. As case studies have long been used to advance deeper learning, these data provide evidence for a broader impact of cases when used in an interdisciplinary setting, especially for those students coming in with the least ability.

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 Alzheimer's 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 role for decorin in the remodeling of myocardial infarction.

Because the small leucine-rich proteoglycan decorin has been implicated in regulation of collagen fibrillogenesis leading to proper extracellular matrix assembly, we hypothesized it could play a key role in cardiac fibrosis following myocardial infarction. In this study we ligated the left anterior descending coronary artery in wildtype and decorin-null mice to produce large infarcts in the anterior wall of the left ventricle. At early stages post-coronary occlusion the myocardial infarction size did not appreciably differ between the two genotypes. However, we found a wider distribution of collagen fibril sizes with less organization and loose packing in mature scar from decorin-null mice. Thus, we tested the hypothesis that these abnormal collagen fibrils would adversely affect post-infarction mechanics and ventricular remodeling. Indeed, scar size, right ventricular remote hypertrophy, and left ventricular dilatation were greater in decorin-null animals compared with wildtype littermates 14 days after acute myocardial infarction. Echocardiography revealed depressed left ventricular systolic function between 4 and 8 weeks post-ischemia in the decorin-null animals. These changes indicate that decorin is required for the proper fibrotic evolution of myocardial infarctions, and that its absence leads to abnormal scar tissue formation. This might contribute to aneurysmal ventricular dilatation, remote hypertrophy, and depressed ventricular function.

Remodeling in myocardium adjacent to an infarction in the pig left ventricle.

Changes in the structure of the "normal" ventricular wall adjacent to an infarcted area involve all components of the myocardium (myocytes, fibroblasts and the extracellular matrix, and the coronary vasculature) and their three-dimensional structural relationship. Assessing changes in these components requires tracking material markers in the remodeling tissue over long periods of time with a three-dimensional approach as well as a detailed histological evaluation of the remodeled structure. The purpose of the present study was to examine the hypotheses that changes in the tissue adjacent to an infarct are related to myocyte elongation, myofiber rearrangement, and changes in the laminar architecture of the adjacent tissue. Three weeks after myocardial infarction, noninfarcted tissue adjacent to the infarct remodeled by expansion along the direction of the fibers and in the cross fiber direction. These changes are consistent with myocyte elongation and myofiber rearrangement (slippage), as well as a change in cell shape to a more elliptical cross section with the major axis in the epicardial tangent plane, and indicate that reorientation of fibers either via "cell slippage" or changes in orientation of the laminar structure of the ventricular wall are quantitatively important aspects of the remodeling of the normally perfused myocardium.