| Summary: |
Rational:With the increasing average life span, age-related cognitive disorders such as Alzheimer's disease(AD)are a major health concern in nowadays. The brain is particularly sensitive to cumulative oxidative damage of proteins, lipids and DNA,which occurs during normal aging process due to the high metabolic demands of the brain tissue and low levels of antioxidant defences. Perturbations of energy metabolism including mitochondrial dysfunction and activation of signalling pathways leading to cell death that culminate in functional deficits are observed in aged and ADbrains. Therefore, important targets for prevention and long-term treatment of early stages of age-related AD should include mitochondrial protection with subsequent reduction of oxidative damage and associated apoptotic signalling.Physical exercise is a widely recommended intervention for most disease conditions, known to
promote brain plasticity and to improve cognitive functions. Regular exercise improves hippocampus plasticity, increasing neurogenesis and angiogenesis, which are coupled with metabolic energetic adaptations such as regulation of glucose uptake.
Results of proteomic and molecular studies revealing exercise-mediated alterations in mitochondrial energy producing systems correlate well with improved mitochondrial activity. Moreover, exercise reversed chronic stress-induced mitochondrial- mediated apoptosis initiation.However, effects of lifelong exercise against deleterious brain mitochondrial sequels associated with aging and AD conditions have not been studied, which makes this submission highly innovative.
Hypothesis:Our work hypothesis is that life-long physical exercise increases brain mitochondrial capacity and decreases vulnerability to induction of the permeability transition and apoptotic signalling. We expect to find a tight correlation between improved mitochondrial function, dynamics and antioxidants with decreased oxidative damage. As a side objective, w  |
Summary
Rational:With the increasing average life span, age-related cognitive disorders such as Alzheimer's disease(AD)are a major health concern in nowadays. The brain is particularly sensitive to cumulative oxidative damage of proteins, lipids and DNA,which occurs during normal aging process due to the high metabolic demands of the brain tissue and low levels of antioxidant defences. Perturbations of energy metabolism including mitochondrial dysfunction and activation of signalling pathways leading to cell death that culminate in functional deficits are observed in aged and ADbrains. Therefore, important targets for prevention and long-term treatment of early stages of age-related AD should include mitochondrial protection with subsequent reduction of oxidative damage and associated apoptotic signalling.Physical exercise is a widely recommended intervention for most disease conditions, known to
promote brain plasticity and to improve cognitive functions. Regular exercise improves hippocampus plasticity, increasing neurogenesis and angiogenesis, which are coupled with metabolic energetic adaptations such as regulation of glucose uptake.
Results of proteomic and molecular studies revealing exercise-mediated alterations in mitochondrial energy producing systems correlate well with improved mitochondrial activity. Moreover, exercise reversed chronic stress-induced mitochondrial- mediated apoptosis initiation.However, effects of lifelong exercise against deleterious brain mitochondrial sequels associated with aging and AD conditions have not been studied, which makes this submission highly innovative.
Hypothesis:Our work hypothesis is that life-long physical exercise increases brain mitochondrial capacity and decreases vulnerability to induction of the permeability transition and apoptotic signalling. We expect to find a tight correlation between improved mitochondrial function, dynamics and antioxidants with decreased oxidative damage. As a side objective, we will also study the impact of exercise on endoplasmic reticulum (ER) stress levels. Specific aims and methods: To confirm our work hypothesis, we will submit rats to running in a free wheel, which is an established rodent model of voluntary physical activity with high physiological relevance, as opposed to forced treadmill running protocols. Intracerebroventricular treatment with streptozoticin (ICV-STZ) is a largely and effective used model of AD in rodents, characterized by numerous neurochemical changes leading to cognitive dysfunction and dementia.Among others, several signs of mitochondrial dysfunction at the level of phosphorylative system and calcium homeostasis, as well as increased cell death signaling are described in this model. Wistar rats will be assigned to different groups. Behavioral tests will be performed to evaluate cognitive function (spatial learning and memory). Isolated cortical and hippocampal mitochondria will be obtained for real-time measurements of phosphorylating system and induction of the cyclosporine A-sensitive transition pore
(mtPTP). Also, several markers of oxidative damage, apoptosis and antioxidants will be measured in mitochondria and/or brain homogenates. Finally, proteins involved in mitochondrial dynamics and ER stress (unfolded protein response-related proteins) will be investigated to confirmed disrupted mitochondrial homeostasis during AD and the protective role of physical activity.
Significance:Important contributions to understand the mitochondrial mechanisms associated with the role of exercise to counteract age- and AD-related brain dysfunc |