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Copyright © Andrea Kurucz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This article has been cited by other articles in PMC. Abstract Alzheimer's disease AD is a neurodegenerative disorder with cognitive impairment. Physical exercise has long been proven to be beneficial in the disorder.
The present study was designed to examine the effect of voluntary exercise on spatial memory, imaging, and pathological abnormalities. Particular focus has been given to the role of heme oxygenase-1 HO-1 —an important cellular cytoprotectant in preserving mental acuity—using an aging rat model of dementia.
Rats in the ARF and ARM groups had free access to a standardized inbuilt running wheel during the 3-month evaluation period.
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The outcomes suggest that voluntary physical exercise mitigates impaired spatial memory and neuropathological changes exhibited by the aging sedentary group, via elevated HO-1 activity, contributing to the antioxidant capacity in the aging brain. Introduction Alzheimer's disease AD is a progressive neurodegenerative disorder, with neuropathology characterized by the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles.
InAlzheimer's Disease International, an organization founded to promote efforts to prevent and treat the disease, issued their World Alzheimer's Report, which estimates that Changes in demographic patterns, principally increasing life expectancy, with resulting increases in elderly populations, have resulted in a concomitant expansion of AD-afflicted individuals and an increased burden on national healthcare systems.
According to Alzheimer's Association, AD is the 6th leading cause of death in the USA, with 1 out of every 3 elderly people succumbing to it in In that year, the estimated fiscal cost of the disease was billion dollars, which is forecast to increase to a trillion dollars annually by These factors notwithstanding, the development of effective countermeasures for AD remains elusive at the time of this writing [ 1 ].
Although comprehensively definitive descriptions of AD pathomechanisms remain undefined, some major contributing factors have been elucidated.
For example, evidence of a signaling cascade triggered by amyloid deposits, resulting in neuroinflammation and microtubule-associated tau protein hyperphosphorylation, is a likely major underlying process contributing to AD pathogenesis [ 2 ].
An element of this phenomenon is amyloid precursor protein APPa transmembrane component of the outer membrane of the cell. Also, the mitochondria is cleaved by three enzymes α- β- and γ-secretases, with variable cleavage outcomes, determined by as-yet undefined factors. Exploration of this enzymatic activity reveals that cleavage by α-secretase prevents amyloid β-formation—and the main products of cleavage by β- and γ-secretases include Aβ40 and Aβ42, which are secreted extracellularly, and may form aggregations that contribute to neurological tissue damage [ 3 — 5 ].
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- This discovery could lead to a test that would help doctors identify patients at greatest risk and help them potentially avert the disease through interventions including diet and exercise.
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Tau protein aggregation is promoted by amyloid β, which may directly or indirectly activate protein kinases, such as GSK3 and CDK5, via elevation of intracellular calcium levels, leading to tau-hyperphosphorylation and aggregate formation [ 67 ]. Once tau aggregation is initiated, the resulting cascade becomes self-sustaining, continuing independently of amyloid β presence [ 2 ].
Rogers et al. Several studies have demonstrated that oxidative stress, mitochondrial dysfunction, and inappropriately high proinflammatory activity synergize to damage macromolecules on which healthy cellular and tissue function are dependent—including nucleic acids, lipids, and proteins, ultimately causing neurodegeneration [ 10 — 12 ].
HO is a major cellular cytoprotectant, the upregulation of which is an early event of the adaptive response to stress [ 13 ].
The correlation between cardiovascular disease and psychosocial factors including concomitant mental disorders as well as personality traits or the effect of social environment has been established in numerous studies aimed at investigating pathogenesis or various clinical endpoints.
In humans, rodents, and many other species, HO exists as two main isoforms: HO-1, an inducible form, and HO-2, which is a constitutively active form. HO-1, also known as heat shock protein Hsp is expressed at increased levels in response to internal or exogenous stress cues, including the following: oxidative stress, ischemia, reperfusion, thermal effects, bacterial lipopolysaccharide, and the presence of hemin, its main substrate, which accumulates in tissues as a result of red blood cell turnover [ 14 journal of diabetes metabolism and its complications.
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HO-2 expression is observed to increase in response to developmental factors, adrenal glucocorticoids, and nitric oxide NO [ 1516 ]. The gene coding for HO-1, HMOX1, has two upstream enhancer regions—E1 and E2—which contain antioxidant-responsive elements supporting the oxidative-inducible nature of this protein [ 17 ].
Maines suggested that HO-1 plays a pivotal role in the earliest phases of homeostatic adaptive responses that have evolved to limit tissue damage, while HO-2 is more likely to act as a housekeeping molecule in ways that contribute to the maintenance of heme homeostasis [ 18 ].
CO, which is a major metabolite resulting from HO-mediated degradation of heme, regulates important mechanisms in the central nervous system.
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These include long-term hippocampal potentiation and neurotransmitter release. HO also functions in the peripheral nervous system to catalyze a diverse range of vital activities, such as the following: nonadrenergic, noncholinergic gastrointestinal relaxation; vasodilation; and inhibition of platelet aggregation. Journal of diabetes metabolism and its complications, the enzyme acts to limit apoptotic depletion of healthy cells in response to oxidative stressors, along with other cytoprotective functions [ 19 — 23 ].
HO-mediated heme degradation produces biliverdin, which is almost immediately reduced to bilirubin BR by biliverdin reductase BVR. Several investigations have demonstrated that accumulation of amyloid β acts to increase HO-1, in a physiologic regulatory feedback process which ameliorates the harmful effects of amyloid β [ 2526 ].
Additionally, many studies which describe the protective role of physical activity as a countermeasure to AD-related neurodegenerative processes include underlying cellular and molecular mechanisms in which HO activity is a potential factor for humans and in animal models of AD [ 27 ].
Insight into the above events is likely to yield improved understanding to AD etiology which, at the time of this writing, remains substantially obscure. Most cases of AD occur spontaneously, with triggering events that are poorly defined or unknown. Several animal models have proven to be journal of diabetes metabolism and its complications investigative tools for research into AD pathogenesis. The most widely used animals for modeling AD are mice and rats.
Due to the lack of complete understanding of AD pathomechanisms, all of these models have significant limitations. However, careful selection of a particular animal model in the context of a particular AD-related hypothesis to be tested may reduce the influence of confounding factors associated with a particular model.
For example, the numerous transgenic mouse models exhibit features that make them particularly useful in characterizing the familial form of AD, while healthy animals that are subjected to treatments such as streptozotocin- STZ- induced neurodegeneration may be used to demonstrate phenotypic characteristics of the spontaneously occurring forms of AD [ 33 ]. The authors of the present investigation selected a model in which neurodegeneration occurred naturally, though advanced age month-old ratsthus avoiding the potentially confounding influences of transgenes or drugs.
The present investigation was structured to test a hypothesis that voluntary recreational physical activity treadmill exercise ameliorates neurodegeneration-related cognitive decline and associated major neuropathological alterations by decreasing oxidative stress via increasing HO-1 activity, thereby preventing neuronal loss in the brain of aging rats. This is the first study to evaluate this possibility using an animal model as a correlation between physical exercise and molecular-biological effects associated with age-related neurodegeneration.
Materials journal of diabetes metabolism and its complications Methods 2. Animals month-old male and female Wistar rats, weighing — grams at the outset of each experiment, were housed two per cage at an ambient temperature of 22—24°C under a 12 h : 12 h light : dark cycle with food and water ad libitum. All groups were maintained in the above described conditions for 3-month periods.
MWM data is here considered to be particularly valuable, since it is one of the most frequently used learning and spatial memory assessments for rodent models, and it is acknowledged to produce reliably reproducible outcomes [ 34 ].
MWM evaluations were conducted as follows: a circular pool, cm in diameter, 50 cm in height, in a small quiet room, is filled with opaque water at room temperature, to a depth of 30 cm, and divided into four quadrants. An invisible platform, 10 cm in diameter, is submerged 1 cm below the surface, in the middle of one of the four quadrants.
The position of the platform is kept unaltered throughout a training session, during which time each animal becomes familiar with structural features and visual cues, memories of which are the basis of the test. Selected visual cues are placed on the inner wall of the pool to indicate the four quadrants and provide navigation reference points, which the rats will remember to varying degrees, depending on their neurological capacity.
MWM tests were carried out during three consecutive days, twice a day before the treatment baselineand after the 3 months of voluntary running on wheels installed in cages. For each trial, the animals were gently put into the water at one of the four starting points that differed for each test—the sequences for which were selected randomly. The tests were scored on the basis of ability of the animals to locate the submerged platform. Each animal was allowed a second rest period on the platform.
If an animal was unable to locate a platform within a a legújabb módszerek iránt a diabétesz 1 gyermek interval, it was gently guided and placed on it. Escape latency time and swimming patterns were measured by a video tracking system EthoVisionNoldus Information Technology, Netherlands.
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Scanner normalization and random correction were applied on the data, and the images were reconstructed with the standard EM iterative algorithm. The pixel size was 0. The system sensitivity is Ellipsoidal 3-dimensional volumes of interest VOI were manually drawn around the edge of the brain journal of diabetes metabolism and its complications by visual inspection using BrainCad software. Rat brains were removed and bisected into two halves.
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The sections were placed on slides, dried at 37°C overnight, then rehydrated using a graded alcohol series, and then stained with hematoxylin for 3 minutes. Sections were rinsed in running tap water for 10 minutes until they turned blue and then stained with eosin for 3 minutes.
Congo red-stained sections were subsequently counterstained with hematoxylin for 3 minutes, rinsed in running tap water to develop blue coloration, washed twice in distilled water, and stained with Congo red for 40 minutes.
The stained sections were subsequently analyzed by light microscopy. Examination of Congo red-stained tissues was conducted using polarized light. Semiquantitative analysis of amyloid pathology was accomplished by first counting the number of amyloid plaques and Congo red-positive vessels as a fraction of the total number of vessels observed in 10 fields, using a 10x objective x magnification. Immunohistochemical Study Immunohistochemistry IHC has been performed according to standardized methods.
In brief, 7 μm thick sections from formalin-fixed, paraffin-embedded blocks have been stained for anti-beta amyloid 1—42 antibody Abcam, 1 : according to the manufacturer's protocol. The stained sections were analyzed by light microscopy. Semiquantitative analysis of amyloid pathology was accomplished by a similar method to that of the Congo red staining. We counted the number of anti-beta amyloid 1—42 antibody-positive vessels as a fraction of the total number of vessels observed in 10 fields, using a 10x objective x magnification.
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Measurement of Heme Oxygenase Activity A widely used and reliable assay for HO-1 activity, based on the reduction of biliverdin into bilirubin, was used for the present study [ 36 ]. The supernatant journal of diabetes metabolism and its complications collected by centrifugation for 30 minutes at 20, ×g at 4°C. Each reaction mixture contained the following in a final volume of 1. Incubation was carried out in the dark at 37°C for 60 minutes.
The reaction was stopped by putting samples on ice. The bilirubin formed was calculated from the difference between optical densities obtained at nm and nm.
One unit of heme oxygenase activity was defined as the amount of bilirubin nmol produced per hour per mg of protein. All data were expressed as means ± SEM. Two data sets were compared with unpaired Student t-test or t-test with Welch's correction if equal variance test was not passed.
All data sets passed the D'Agostino-Pearson omnibus normality test. Results 3. Assessments based on swim time to find submerged platforms escape latency were followed with a tracking system. Escape latency scores revealed a significant correlation between voluntary exercises on the three training days of the MWM test protocol Figure 1.
However, animals in the aged running groups both males and females were more likely to find the platform within decreasing time compared to the sedentary aging groups mean differences: Day 1: