Showing papers on "Aging brain published in 2004"

RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid β-Peptide Clearance Through Transport Across the Blood–Brain Barrier

Abstract: Accumulation of amyloid beta-peptide (Abeta) in the central nervous system (CNS) may initiate pathogenic cascades mediating neurovascular and neuronal dysfunctions associated with the development of cerebral beta-amyloidosis and cognitive decline in patients with Alzheimer disease (AD) and with related familial cerebrovascular disorders. Whether Abeta-related pathology in the CNS is reversible or not and what key therapeutic targets are controlling Abeta/amyloid levels in the aging brain remain debatable. In this article, we summarize recent evidence why the receptor for advanced glycation end products and low-density lipoprotein receptor related protein 1 in the vascular CNS barriers are critical for regulation of Abeta homeostasis in the CNS and how altered activities in these 2 receptors at the blood-brain barrier may contribute to the CNS Abeta accumulation resulting in neuroinflammation, disconnect between the cerebral blood flow and metabolism, altered synaptic transmission, neuronal injury, and amyloid deposition into parenchymal and neurovascular lesions. We briefly discuss the potential of advanced glycation end products and low-density lipoprotein receptor related protein 1-based therapeutic strategies to control brain Abeta in animal models of AD and ultimately in patients with AD and related familial cerebrovascular beta-amyloidoses.

Free Radicals: Key to Brain Aging and Heme Oxygenase as a Cellular Response to Oxidative Stress

Abstract: Aging is one of the unique features in all organisms. The impaired functional capacity of many systems characterizes aging. When such impairments occur in the brain, the susceptibility to neurodegenerative diseases amplifies considerably. The free radical theory of aging posits that the functional impairments in brains are due to the attack on critical cellular components by free radicals, reactive oxygen species, and reactive nitrogen species produced during normal metabolism. In this review, we examine this concept based on the parameters of oxidative stress in correlation to aging. The parameters for lipid peroxidation are phospholipid composition, reactive aldehydes, and isoprostanes. The parameters for protein oxidation are protein carbonyl levels, protein 3-nitrotyrosine levels, electron paramagnetic resonance, and oxidative stress-sensitive enzyme activities. We conclude that free radicals are, at least partially, responsible for the functional impairment in aged brains. The aging brain, under oxidative stress, responds by induction of various protective genes, among which is heme oxygenase. The products of the reaction catalyzed by heme oxygenase, carbon monoxide, iron, and biliverdin (later to bilirubin) each have profound effects on neurons. Although there may be other factors contributing to brain aging, free radicals are involved in the damaging processes associated with brain aging, and cellular stress response genes are induced under free radical oxidative stress. Therefore, this review supports the proposition that free radicals are, indeed, a key to brain aging.

Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain.

Abstract: Principal mental disorders affecting the geriatric population include dementia and depression. A lack of trophic support is thought to contribute to the pathology of these disorders. Physical activity and antidepressant treatment increase the expression of brain-derived neurotrophic factor (BDNF) in the young rat hippocampus. Herein, we investigated the responsiveness of the aging rat hippocampus to antidepressant treatment and voluntary exercise. In situ hybridization revealed that, in young animals, exercise, antidepressant treatment, or their combination elevated BDNF mRNA levels in several hippocampal regions, most notably in the CA3, CA4, and dentate gyrus (DG). This effect was rapid (detectable at 2 days) and sustainable to 20 days. In aged (22-month-old) rats, hippocampal responsiveness to antidepressant treatment and exercise was also rapid and sustainable, but evident mostly in the CA1 and CA2. Daily swimming also revealed that small amounts of activity led to marked elevations in hippocampal BDNF mRNA. The differences in regional patterns of BDNF mRNA elevations between young and aged animals observed with running were maintained with this different exercise modality. Our results indicate that the aged brain is responsive to exercise and antidepressant treatment, and changes in regional response patterns may reflect shifts in hippocampal physiology during the lifespan.

Intracerebral Hemorrhage Effects of Aging on Brain Edema and Neurological Deficits

Abstract: Background and Purpose— Intracerebral hemorrhage (ICH) is mostly a disease of the elderly, but most current experimental ICH models have used young animals. Age is an important factor in other forms of brain injury, affecting microglia and astrocyte reactions and plasticity. Therefore, the present study investigated the effects of aging on brain injury after ICH. Methods— Young and aged (3 and 18 months old, respectively) male Sprague-Dawley rats received an intracerebral infusion of 100 μL autologous blood. Age-related changes in brain swelling, glial reaction, stress protein (heat shock proteins [HSPs] 27 and 32), and neurological deficits were examined. Results— Brain swelling was more severe in old rats compared with young rats at 3 days after ICH ( P P P Conclusions— ICH causes more severe brain swelling and neurological deficits in old rats. Clarification of the mechanisms of brain injury after ICH in the aging brain should help develop new therapeutic strategies for hemorrhagic brain injury.

Neural stem cells as therapeutic agents for age-related brain repair.

Abstract: Summary Neurogenesis occurs in two germinal centres of the adult brain and persists with increasing age, although at a reduced level. This observation, that the mature brain can support neurogenesis, has given rise to the hope that neural stem cells could be used to repair the brain by repopulating regions suffering from neuronal loss as a result of injury or disease. The aging brain is vulnerable to mild cognitive impairment, increasing incidence of stroke, and a variety of neurodegenerative diseases. However, most studies to date have focused on the young adult brain, and relatively little information is available about the regulation of neurogenesis in the aged brain or the potential of using neural stem cells to repair the aged brain. This review summarizes the current state of knowledge on neurogenesis in the young adult brain and discusses the information available on age-related changes in neurogenesis. Possible therapeutic strategies using neural stem cells for repair of the aging brain are considered.

Effects of age and caloric restriction on brain neuronal cell death/survival.

Abstract: Aging may pose a challenge to the central nervous system, increasing its susceptibility to apoptotic events. Recent findings indicate that caloric restriction (CR) may have a profound effect on brain function and vulnerability to injury and diseases, by enhancing neuroprotection, stimulating the production of new neurons, and increasing synaptic plasticity. Apoptosis and apoptotic regulatory proteins in the brain frontal cortex of 6-month-old ad libitum fed (6AD), 26-month-old ad libitum fed (26AD), and 26-month-old caloric-restricted (26CR) male Fischer 344 rats (40% restriction compared to ad libitum fed) were investigated. Levels of Poly-ADP ribose polymerase (PARP-DNA repair enzyme; its cleaved 89 kDA fragment is a marker of apoptosis), cytoplasmic histone-associated DNA fragments, and X chromosome-linked inhibitor of apoptosis (XIAP--an endogenous apoptosis inhibitor) were determined. A significant age-associated increase in PARP was found, which was ameliorated in the frontal cortices of the CR rats. No significant differences in cytoplasmic histone-associated DNA fragments with age or with CR were observed. XIAP levels significantly increased with age in the brains of the ad libitum animals, while CR animals exhibited the highest levels of this inhibitor compared to all groups. Our findings suggest that caloric restriction may provide neuroprotection to the aging brain by preserving DNA repair enzymes in their intact form, and/or upregulating specific antiapoptotic proteins involved in neuronal cell death.

Activation of calpain‐1 in myelin and microglia in the white matter of the aged rhesus monkey

Abstract: Ultrastructural disruption of myelin sheaths and a loss of myelin with age are well-documented phenomena in both the human and rhesus monkey. Age-dependent activation of calpain-1 (EC 3.4.22.52) has been suggested as a plausible mechanism for increased proteolysis in the white matter of the rhesus monkey. The present study documents activation of calpain-1 throughout brain white matter in aged animals, evidenced by immunodetection of the activated enzyme as well as a calpain-derived spectrin fragment in both tissue section and Triton X-100-soluble homogenate of subcortical white matter from the frontal, temporal, and parietal lobes. Separation of myelin fractions from brain stem tissue into intact and floating myelin confirmed previous reports of an age-related increase in activated calpain-1 in the floating fraction. Measurements of calpain-1 activity using a fluorescent substrate revealed an age-related increase in calpain-1 proteolytic activity in the floating myelin fraction consistent with immunodetection of the activated enzyme in this fraction. Double-immunofluorescence demonstrated co-localization of activated calpain-1 with human leukocyte antigen-DR (HLA-DR), a marker for activated microglia, suggesting that these cells represent the major source of the increase in activated calpain-1 in the aging brain. These data solidify the role of calpain-1 in myelin protein metabolism and further implicate activated microglia in the pathology of the aging brain.

Combining growth factors, stem cells, and gene therapy for the aging brain.

Abstract: Stem cells have been suggested as a possible "fountain of youth" for replacing tissues lost during aging. In the brain, replacing lost neurons is a challenge, as they have to then be reconnected with their appropriate targets. Perhaps a more realistic and practical strategy for affecting the aging process would be to prevent the loss of neurons from occurring, thus retaining intact circuitry. Glial cell line-derived neurotrophic factor (GDNF) can reverse some aspects of aging in the monkey. Additionally, we have recently shown that GDNF directly infused into the human brain has significant effects on the symptoms of Parkinson disease. Human neural stem cells can be cultured, genetically modified, and transplanted. As such, these cells are ideal for ex vivo gene therapy, and may be used in the future as "minipumps" to release GDNF in vivo to protect aging neurons. Using such an approach could delay the effects of aging in the brain, giving a better quality of life. Stem cells might not be the fountain of youth, but provide a fountain of youth through the release of growth factors such as GDNF.

Retardation of Brain Aging by Chronic Treatment with Melatonin

Abstract: Slowing the functional decline in the aging brain is not only relevant to nonpathological senescence but also to a broad range of neurodegenerative diseases. Although disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are not found in the young adult, they gradually manifest with increasing age. AD, in particular, is an increasing major public health concern as the population ages; therapies that delay disease onset will markedly reduce overall disease prevalence. Aging of the brain has been repeatedly associated with cumulative oxidative damage to macromolecules and to abnormal levels of inflammatory activity. Melatonin has attained increasing prominence as a candidate for ameliorating these changes occurring during senescence. Recent research has focused on supplementation with dietary melatonin designed to elucidate the specific key intracellular targets of age-related inflammatory events, and the optimal means of affording protection of these targets. This report summarizes the progress made in this area.

Motor and cognitive recovery induced by bone marrow stem cells grafted to striatum and hippocampus of impaired aged rats: functional and therapeutic considerations.

Abstract: Impairments in motor coordination and cognition in normal and pathological aging are often accompanied by structural changes, that is, loss of synapses and neurons. Also, it has been shown recently that bone marrow stem cells can give origin to cells of different tissues, including neural cells. Given the therapeutic implications of increasing health and functional possibilities in the aged brain, we have tested the effects of rat femur bone marrow stem cells (rBMSCs) grafting to the striatum hippocampus of aged rats with motor or cognitive deficits, respectively. Bone marrow cells were transduced with an adenovirus driving the expression of green fluorescence protein (GFP) and other classic stains to determine their migration, engraftment, differentiation, and associated behavioral recovery. Five weeks after it, control and grafted rats were re-evaluated with the Morris Water Maze test, Passive avoidance, open-field, motor coordination, and Marshall tests and perfused. Brains were processed and analyzed for fluorescent protein expression. GFP was detected in cells with some differentiation degree into neural-like cells. Their exact phenotype is yet to be determined. A significant functional recovery was observed 6 weeks after grafting, suggesting a trophic interaction between rBMSCs and the aged/dystrophic host brain, or with the host brain progenitor cells and/or by increasing the number of functional cells at striatum or hippocampus, suggesting that the aging brain keeps its functional plasticity as well as that BMSCs are interesting candidates for cell replacement therapies in neurodegenerative disorders.

Aging changes in the human brain: A histochemical and immunohistochemical study

Abstract: There are very few studies on neuropathological changes of aging in the Indian population. In the present study, the incidence of aging changes in 20 non-demented elderly humans above the age of 55 years were observed. The incidence of neurofibrillary tangles (NFT) increased from 20% in 50-55-year-olds to 80% in 55-year-olds and over. Senile plaques (SP) increased from 20% in 50-55-year-olds to 80% in 55-60-year-olds and 40% in 60-year-olds and over. The results of immunohistochemistry to label the NFT (Tau) and SP (beta-amyloid) were comparable to the Bielchowsky's modified silver methanamine method. The incidence of age related changes and their antigenic character in the limited sample studied from north-west India appear to be comparable to those from the southern part of India and Western hemisphere.

Morphological and quantatitive capillary changes in aging human brain

Abstract: Objective To investigate morphological changes of capillary in aging brain and explore the role of vascular factor in brain aging. Methods Twenty-eight brains of individuals (mean age 65 years) who died without clinical or pathological involvement of nervous system and 6 brains of Alzheimer's disease (AD) patients (mean age 83 years) were obtained at autopsy. Sections from frontal lobe, occipital lobe, striatum and hippocampus of normal subjects and sections from hippocampus of AD patients were used for hematoxylin eosin (HE), lox fast blue (LFB), toluidine blue stains and ulex europaeus agglutinin (UEA) immunostaining. After observations of morphological changes of neuron and capillary, computer-aid image analysis was performed to quantify numerical density and area density of neuron and capillary in frontal lobe, occipital lobe, putamen, CA3 sector of normal subjects and CA3 sector of AD patients. Numerical ratio and area ratio of neuron and capillary were then calculated. Correlations between neuron/capillary ratio and age were estimated using Pearson's correlation test. Difference of neuron/capillary ratio in CA3 sectors between AD patients and advanced aged normal subjects (> 75 years) was analyzed with Student's t-test. Results Several pathological microvascular changes, including increased tortuosity, looping, bundling, stringing, and effacement of endothelia were seen in aged subjects and more prevalent in AD patients. Numerical ratio and area ratio of neuron and capillary of frontal lobe, occipital lobe and putamen significantly increased with age in normal aging subjects. Conclusions Morphological changes and relative decrease in number and capacity of capillary in aging brain may reduce cerebral blood flow and metabolism, and consequently result in functional impairment of aging brain. Vascular factors may play an important role in the development of brain aging.

The Aging Brain — the Burden of Life (?)

Abstract: Increasing life expectancy has raised health problems with respect to „normal”aging, and particularly to age related disorders. This holds true for several brain diseases in middle, and more frequently, in old age such as stroke (brain ischemia), Parkinson’s disease and dementia of either vascular origin or sporadic Alzheimer type.