Summary
Aging is a complex, multifactorial process. One of the features of normal aging of the brain is a decline in cognitive functions and much experimental attention has been devoted to ...understanding this process. Evidence accumulated in the last decade indicates that such functional changes are not due to gross morphological alterations, but to subtle functional modification of synaptic connectivity and intracellular signalling and metabolism. Such synaptic modifications are compatible with a normal level of activity and allow the maintenance of a certain degree of functional reserve. This is in contrast to the changes in various neurodegenerative diseases, characterized by significant neuronal loss and dramatic and irreversible functional deficit. This whole special issue has been initiated with the intention of focusing on the processes of normal brain aging. In this review, we present data that shows how subtle changes in Ca2+ homeostasis or in the state of various Ca2+‐dependent processes or molecules, which occur in aging can have significant functional consequences.
Normal brain ageing: models and mechanisms Toescu, Emil C
Philosophical transactions - Royal Society. Biological sciences,
12/2005, Letnik:
360, Številka:
1464
Journal Article
Recenzirano
Odprti dostop
Normal ageing is associated with a degree of decline in a number of cognitive functions. Apart from the issues raised by the current attempts to expand the lifespan, understanding the mechanisms and ...the detailed metabolic interactions involved in the process of normal neuronal ageing continues to be a challenge. One model, supported by a significant amount of experimental evidence, views the cellular ageing as a metabolic state characterized by an altered function of the metabolic triad: mitochondria-reactive oxygen species (ROS)-intracellular Ca2+. The perturbation in the relationship between the members of this metabolic triad generate a state of decreased homeostatic reserve, in which the aged neurons could maintain adequate function during normal activity, as demonstrated by the fact that normal ageing is not associated with widespread neuronal loss, but become increasingly vulnerable to the effects of excessive metabolic loads, usually associated with trauma, ischaemia or neurodegenerative processes. This review will concentrate on some of the evidence showing altered mitochondrial function with ageing and also discuss some of the functional consequences that would result from such events, such as alterations in mitochondrial Ca2+ homeostasis, ATP production and generation of ROS.
Calcium and normal brain ageing Toescu, Emil C; Vreugdenhil, Martin
Cell calcium (Edinburgh),
02/2010, Letnik:
47, Številka:
2
Journal Article
Recenzirano
Abstract Normal brain ageing is associated with a varying degree of cognitive impairment. Although ageing is a complex, multifactorial process, and no single process could explain the ageing ...phenotype, a number of processes and homeostatic systems, due to their central roles in cellular physiology, have been identified as playing important roles in the process of normal ageing. In this review we revisit the basic tenets of the Ca2+ hypothesis of neuronal ageing and stress the major conceptual changes that occurred between the time of its original proposal and now, in particular in respect to the extent of neuronal loss in normal ageing. We provide a general overview of the most important ageing-associated changes in neuronal Ca2+ homeostasis and then discuss in some detail how such homeostatic changes are affecting basic neuronal properties, such as intrinsic excitability and how, by extension, such changes could lead to significant perturbations in the activity of whole neuronal network ensembles. Since some of these network activities, such as the synchronisation of neuronal activity in the gamma frequency range, have been linked to learning and cognition, understanding the metabolic substrates and homeostatic dysregulation that underpin them could provide a novel basis for attempts at counteracting the cognitive decline of older individuals.
Blood-brain barrier alterations in ageing and dementia Popescu, Bogdan O; Toescu, Emil C; Popescu, Laurenţiu M ...
Journal of the neurological sciences,
08/2009, Letnik:
283, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Abstract The current pathogenic scenarios of different types of dementia are based on a number of common mechanisms of neurodegeneration, such as accumulation of abnormal proteins (within or outside ...cells), mitochondrial dysfunction and oxidative stress, calcium homeostasis dysregulation, early synaptic disconnection and late apoptotic cell death. Ageing itself is associated with mild cognitive deterioration, probably due to subtle multifactorial changes resulting in a global decrease of a functional brain reserve. Increased age is a risk factor for neurodegeneration and key pathological features of dementia can also be found in aged brains. One of the underexplored brain structures in ageing and dementia is the blood-brain barrier (BBB), a complex cellular gate which regulates tightly the transport of molecules into and from the central nervous system. Disruption of this barrier is now increasingly documented not only in brain vascular disease but also in ageing and neurodegenerative disorders. To date, such evidence points mainly at an association between various dementia forms and disruption of the BBB. But, in reviewing such results, and taking into account the exquisite sensitivity of neuronal function to the composition of the interstitial brain fluid (IBF), which is regulated by the BBB, we would like to propose the existence of a possible causal link between alterations of BBB and conditions associated with cognitive decline.
Understanding the cellular mechanisms that characterize the functional changes of the aged brain is an ongoing and formidable challenge for the neuroscience community. Evidence now links changes in ...Ca(2+) influx and homeostasis with perturbations induced by the aging process in the function of the main intracellular organelles involved in Ca(2+) regulation: the endoplasmic reticulum and mitochondria. New perspectives are also offered by recent gene microarray studies, illustrating the multifactorial nature of the aging process.
S1P (sphingosine 1-phosphate) receptor expression and the effects of S1P on migration were studied in one papillary (NPA), two follicular (ML-1, WRO) and two anaplastic (FRO, ARO) thyroid cancer cell ...lines, as well as in human thyroid cells in primary culture. Additionally, the effects of S1P on proliferation, adhesion and calcium signalling were addressed in ML-1 and FRO cells. All cell types expressed multiple S1P receptors. S1P evoked intracellular calcium signalling in primary cultures, ML-1 cells and FRO cells. Neither proliferation nor migration was affected in primary cultures, whereas S1P partly inhibited proliferation in ML-1 and FRO cells. Low nanomolar concentrations of S1P inhibited migration in FRO, WRO and ARO cells, but stimulated ML-1 cell migration. Consistently, S1P1 and S1P3, which mediate migratory responses, were strongly expressed in ML-1 cells, and S1P2, which inhibits migration, was the dominating receptor in the other cell lines. The migratory effect in ML-1 cells was mediated by G(i) and phosphatidylinositol 3-kinase. Both S1P and the S1P1-specific agonist SEW-2871 induced Akt phosphorylation at Ser473. However, SEW-2871 failed to stimulate migration, whereas the S1P1/S1P3 antagonist VPC 23019 inhibited S1P-induced migration. The results suggest that aberrant S1P receptor expression may enhance thyroid cancer cell migration and thus contribute to the metastatic behaviour of some thyroid tumours.
Abstract Every cell or neuronal type utilizes its own specific organization of its Ca2+ homeostasis depending on its specific function and its physiological needs. The magnocellular neurones, with ...their somata situated in the supraoptic and paraventricular nuclei of the hypothalamus and their nerve terminals populating the posterior hypophysis (neural lobe) are a typical and classical example of a neuroendocrine system, and an important experimental model for attempting to understand the characteristics of the neuronal organization of Ca2+ homeostasis. The magnocellular neurones synthesize, in a cell specific manner, two neurohormones: arginine-vasopressin (AVP) and oxytocin (OT), which can be released, in a strict Ca2+ -dependent manner, both at the axonal terminals, in the neural lobe, and at the somatodendritic level. The two types of neurones show also distinct type of bioelectrical activity, associated with specific secretory patterns. In these neurones, the Ca2+ homeostatic pathways such as the Na+ /Ca2+ exchanger (NCX), the endoplasmic reticulum (ER) Ca2+ pump, the plasmalemmal Ca2+ pump (PMCA) and the mitochondria are acting in a complementary fashion in clearing Ca2+ loads that follow neuronal stimulation. The somatodendritic AVP and OT release closely correlates with intracellular Ca2+ dynamics. More importantly, the ER Ca2+ stores play a major role in Ca2+ homeostatic mechanism in identified OT neurones. The balance between the Ca2+ homeostatic systems that are in the supraoptic neurones differ from those active in the terminals, in which mainly Ca2+ extrusion through the Ca2+ pump in the plasma membrane and uptake by mitochondria are active. In both AVP and OT nerve terminals, no functional ER Ca2+ stores can be evidenced experimentally. We conclude that the physiological significance of the complexity of Ca2+ homeostatic mechanisms in the somatodendritic region of supraoptic neurones and their terminals can be multifaceted, attributable, in major part, to their specialized electrical activity and Ca2+ -dependent neurohormone release.
Abstract Prenatal alcohol exposure is associated with microencephaly, cognitive and behavioral deficits, and growth retardation. Some of the mechanisms of ethanol-induced injury, such as high level ...oxidative stress and overexpression of pro-apoptotic genes, can increase the sensitivity of fetal neurons towards hypoxic/ischemic stress associated with normal labor. Thus, alcohol-induced sequelae may be the cumulative result of direct ethanol toxicity and increased neuronal vulnerability towards metabolic stressors, including hypoxia. We examined the effects of ethanol exposure on the fetal cerebellar granular neurons׳ susceptibility to hypoxic/hypoglycemic damage. A chronic ethanol exposure covered the entire prenatal period and 5 days postpartum through breastfeeding, a time interval partially extending into the third-trimester equivalent in humans. After a binge-like alcohol exposure at postnatal day 5, glutamatergic cerebellar granule neurons were cultured and grown for 7 days in vitro , then exposed to a 3-h oxygen–glucose deprivation to mimic a hypoxic/ischemic condition. Cellular viability was monitored by dynamic recording of propidium iodide fluorescence over 20 h reoxygenation. We explored differentially expressed genes on microarray data from a mouse embryonic ethanol-exposure model and validated these by real-time PCR on the present model. In the ethanol-treated cerebellar granule neurons we find an increased expression of genes related to apoptosis ( Mapk8 and Bax ), but also of genes previously described as neuroprotective ( Dhcr24 and Bdnf ), which might suggest an actively maintained viability. Our data suggest that neurons exposed to ethanol during development are more vulnerable to in vitro hypoxia/hypoglycemia and have higher intrinsic death susceptibility than unexposed neurons.
Abstract Oscillations in hippocampal neuronal networks in the gamma frequency band have been implicated in various cognitive tasks and we showed previously that aging reduces the power of such ...oscillations. Here, using submerged hippocampal slices allowing simultaneous electrophysiological recordings and imaging, we studied the correlation between the kainate-evoked gamma oscillation and mitochondrial activity, as monitored by rhodamine 123. We show that the initiation of kainate-evoked gamma oscillations induces mitochondrial depolarization, indicating a metabolic response. Aging had an opposite effect on these parameters: while depressing the gamma oscillation strength, it increases mitochondrial depolarization. Also, in the aged neurons, kainate induced significantly larger Ca2+ signals. In younger slices, acute mitochondrial depolarization induced by low concentrations of mitochondrial protonophores strongly, but reversibly, inhibits gamma oscillations. These data indicating that the complex network activity required by the maintenance of gamma activity is susceptible to changes and modulations in mitochondrial status.
Calcium and neuronal ageing Verkhratsky, Alexej; Toescu, Emil C.
Trends in neurosciences (Regular ed.),
1998, 1998-Jan, 1998-1-00, 19980101, Letnik:
21, Številka:
1
Journal Article
Recenzirano
Brain ageing is associated with a marked decline in mental faculties. One hypothesis postulates that sustained changes in the regulation of intracellular Ca
2+ concentration, Ca
2+
i, are the major ...cause of neuronal degeneration. This `calcium hypothesis' is supported by demonstrations of the impairment in aged neurones of molecular cascades that regulate Ca
2+
i. However, the number of direct measurements of Ca
2+
i in senescent neurones is limited, and the hypothesis cannot be regarded as fully confirmed. Furthermore, physiological brain ageing, at least in certain regions, need not necessarily be a degenerative process accompanied by neuronal loss.
Pharmacological manipulation of Ca
2+ entry has been shown to be effective in increasing some aspects of cognitive function of the aged brain.
Therefore, further exploration of Ca
2+ homeostasis and signalling might reveal the mechanisms involved in the age-dependent decline in neuronal performance, and might aid the search for new therapeutic treatments.