Prospects for research on the modulation of gene activity during brain aging

This brief review is concerned with prospects of the role of modulated gene expression in the brain during aging and in two age-related neurological diseases: Parkinson's and Alzheimer's diseases. Two key mechanisms involved in the disturbance of neuronal function during aging, i. e. deafferentation syndromes (as a result of the impairment of afferent influences) and steroid-induced neuronal changes, have been studied. The author suspects that many aspects of cell aging in the brain represent the influence of the environmental factors. The conception of new therapeutic approaches to the treatment of Alzheimer's disease has been developed.     

ApoE receptor 2 controls neuronal survival in the adult brain

A central pathogenic feature of neurodegenerative diseases and neurotrauma is the death of neurons. A mechanistic understanding of the factors and conditions that induce the dysfunction and death of neurons is essential for devising effective treatment strategies against neuronal loss after trauma or during aging. Because Apolipoprotein E (ApoE) is a major risk factor for several neurodegenerative diseases, including Alzheimer's disease , a direct or indirect role of ApoE receptors in the disease process is likely. Here we have used gene targeting in mice to investigate possible roles of ApoE receptors in the regulation of neuronal survival. We demonstrate that a differentially spliced isoform of an ApoE receptor, ApoE receptor 2 (Apoer2), is essential for protection against neuronal cell loss during normal aging. Furthermore, the same splice form selectively promotes neuronal cell death after injury through mechanisms that may involve serine/threonine kinases of the Jun N-terminal kinase (JNK) family. These findings raise the possibility that ApoE and its receptors cooperatively regulate common mechanisms that are essential to neuronal survival in the adult brain.     

Neuronal--glial interactions during development and aging.

Integration of the central nervous system is an expression of cerebral homeostasis that is essential for the internal ability of the organism to adapt to its changing environment throughout life. It is generally accepted that neurons undergo no further division after differentiation, whereas glial cells continue to proliferate throughout life. The increase in glial cells with advanced age may reflect a compensatory process of the brain to overcome neuronal loss or neuronal functional changes that may occur with age. Therefore, these neuronal-glial interactions during development and aging may play a key role in the integrative capacity of the brain. One of the mechanisms contributing to brain stability is the blood-brain barrier, which regulates the neuronal-glial microenvironment in the mature organism. Neuronal intercommunication is mediated via neurotransmitter substances and a shift may occur from excitation to inhibition and vice versa in some CNS areas with aging. Studies of some aspects of cholinergic, monoaminergic and amino acid neurotransmission show that their maturational patterns are CNS-area specific and that some neurotransmitter processes decline with advanced age. Glial cells, besides participating in the regulation of extraneuronal environment, are also proposed to be involved in neurotransmission mechanisms in the adult and aging CNS and since they are the major CNS cellular compartment that changes with age they may thus contribute significantly to the maintenance of CNS integrative ability and adaptation with age.     

Parkinson disease: from pathology to molecular disease mechanisms

Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.     

Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.     

Hippocampal Extracellular Matrix Levels and Stochasticity in Synaptic Protein Expression Increase with Age and Are Associated with Age-dependent Cognitive Decline

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wild-type mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits, we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed robust and progressive up-regulation over time. This was confirmed by immunoblotting and histochemical analysis, which indicated that the increased levels of hippocampal extracellular matrix might limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance in old age.As the proportion of aged individuals in our population continues to grow, we are faced with an increase in age-related health problems. Brain aging invariably leads to functional decline and impairments in cognitive function and motor skills, which can seriously affect quality of life. A better understanding of the neurobiological mechanisms underlying age-related cognitive decline is crucial to facilitate maintenance of cognitive health in the elderly and to reveal potential causes of highly prevalent age-related forms of dementia, in particular Alzheimer disease, in which cognitive decline is severely impaired by yet unknown mechanisms.Several studies showed that normal brain aging is associated with subtle morphological and functional alterations in specific neuronal circuits (1, 2) and that reduced cognitive function with increasing age is likely due to synaptic dysfunction (3). Increasing evidence supports the idea that alterations in hippocampal activity are correlated with deficits in learning and memory in healthy aging humans (4, 5). In addition, rodent models of healthy aging demonstrate strong correlations between impaired performance in learning and memory tests and disturbed hippocampal network activity (6, 7). Electrophysiological studies provide additional evidence that age-related disturbances in the hippocampus involve changes in the principal cellular features of learning and memory, synaptic long-term potentiation and long-term depression (8, 9). Together, these observations suggest that a decline in hippocampal synaptic efficacy and plasticity plays a critical role in age-dependent cognitive impairment.Aging is also the primary risk factor for Alzheimer disease, which clinically manifests as severe and accelerated age-dependent cognitive decline (10). Genetic causes of familial early-onset Alzheimer disease all point to a key role in disease etiology for increased brain levels of the protein amyloid-β (11). Familial Alzheimer disease, however, is rare, and it is likely that increased amyloid-β levels in sporadic Alzheimer disease result from age-dependent and/or genetically determined alterations in the expression of other genes or proteins (12, 13). Thus, the identification of molecular mechanisms of normal brain aging might also contribute to our understanding of cognitive decline under pathological conditions, in particular in Alzheimer disease.Although the exact mechanisms underlying brain aging remain to be fully determined, they likely include changes at the molecular, cellular, and neuronal-network levels. In particular, characterization of alterations in the molecular composition and dynamics of hippocampal synapses could potentially reveal important aspects of the underlying mechanisms of brain aging. Age-related changes in global hippocampal gene and protein expression have been investigated previously (14, 15), but these studies were not geared to identify the specific synaptic molecular substrates of brain aging. Here, we made use of iTRAQ¹ technology and high-coverage mass spectrometry to study the effects of aging on the proteomic composition of mouse hippocampal synaptosomes. We investigated the synaptic proteomes of individual mice at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Our findings show that both specific changes and increased variance in synaptic protein expression are associated with age-related cognitive decline.     

Allostasis,Allostatic Load,and the Aging Nervous System: Role of Excitatory Amino Acids and Excitotoxicity

The adaptive responses of the body to challenges, often known as "stressors", consists of active responses that maintain homeostasis. This process of adaptation is known as "allostasis", meaning "achieving stability through change". Many systems of the body show allostasis, including the autonomic nervous system and hypothalamo-pituitary-adrenal (HPA) axis and they help to re-establish or maintain homeostasis through adaptation. The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters. When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body that has been termed "allostatic load". Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Circulating stress hormones play a key role, and, in the hippocampus, excitatory amino acids and NMDA receptors are important mediators of neuronal atrophy. The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined. Yet, at the same time, excitatory amino acids and NMDA receptors mediate important types of plasticity in the hippocampus. Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience. This review discusses the current status of work on underlying mechanisms for these effects.     

Biological timing and the clock metaphor: oscillatory and hourglass mechanisms

Living organisms have developed a multitude of timing mechanisms--"biological clocks." Their mechanisms are based on either oscillations (oscillatory clocks) or unidirectional processes (hourglass clocks). Oscillatory clocks comprise circatidal, circalunidian, circadian, circalunar, and circannual oscillations--which keep time with environmental periodicities--as well as ultradian oscillations, ovarian cycles, and oscillations in development and in the brain, which keep time with biological timescales. These clocks mainly determine time points at specific phases of their oscillations. Hourglass clocks are predominantly found in development and aging and also in the brain. They determine time intervals (duration). More complex timing systems combine oscillatory and hourglass mechanisms, such as the case for cell cycle, sleep initiation, or brain clocks, whereas others combine external and internal periodicities (photoperiodism, seasonal reproduction). A definition of a biological clock may be derived from its control of functions external to its own processes and its use in determining temporal order (sequences of events) or durations. Biological and chemical oscillators are characterized by positive and negative feedback (or feedforward) mechanisms. During evolution, living organisms made use of the many existing oscillations for signal transmission, movement, and pump mechanisms, as well as for clocks. Some clocks, such as the circadian clock, that time with environmental periodicities are usually compensated (stabilized) against temperature, whereas other clocks, such as the cell cycle, that keep time with an organismic timescale are not compensated. This difference may be related to the predominance of negative feedback in the first class of clocks and a predominance of positive feedback (autocatalytic amplification) in the second class. The present knowledge of a compensated clock (the circadian oscillator) and an uncompensated clock (the cell cycle), as well as relevant models, are briefly re viewed. Hourglass clocks are based on linear or exponential unidirectional processes that trigger events mainly in the course of development and aging. An important hourglass mechanism within the aging process is the limitation of cell division capacity by the length of telomeres. The mechanism of this clock is briefly reviewed. In all clock mechanisms, thresholds at which "dependent variables" are triggered play an important role.     

Estudio de la vulnerabilidad neuronal selectiva en el sistema nervioso central humano

Introduction

The concept of ‘selective neuronal vulnerability’ refers to the differential sensitivity of neuronal populations in the nervous system to stresses that cause cell damage and lead to neurodegeneration. Because oxidative stress play a causal role in the physiological aging process, and it is often invoked as an aetiopathogenic and/or pathophysiological mechanism for neurodegeneration, in the present work we propose that the molecular bases of selective neuronal vulnerability is linked with cell adaptations related to oxidative stress.

Material and methods

The grey substance of 5 different regions from healthy human subjects (n = 7) were selected: i) to evaluate their membrane fatty acid profile by chromatographic methods, ii) to determine their membrane susceptibility to peroxidation, and iii) to recognise potential mechanisms involved in its regulation.

Results

The results showed significant inter-regional differences in the fatty acid profile, basically due to the content of mono- and highly polyunsaturated fatty acids; changes that, in turn, induce significant differences in theirs susceptibilities to peroxidation, as well as differences that can be ascribed to the desaturase activity.

Conclusion

Thus, the cross-regional comparative approach seems to confirm the idea that the level of cell membrane unsaturation may be a key trait associated with selective neuronal vulnerability.     

The Role of Neurotrophins in Brain Aging: A Perspective in Honor of Regino Perez-Polo

During brain aging and progression of Alzheimer’s disease, the levels of Aβ and proinflammatory cytokines accumulate very early in the pathogenic process prior to any major degenerative changes. Accumulation of these molecules may impair with signal transduction pathways critical for neuronal health. Neurotrophin signaling is a critical mechanism involved in synaptic plasticity, learning and memory and neuronal health. We have recently shown that exposure to low levels of Aβ impairs BDNF trkB signal transduction, suppressing the Ras/ERK, and the PI3-K/Akt pathways but not the PLCγ pathway. As a result, downstream regulation of gene expression and neuronal viability are impaired. Recently, we have found that at least three agents – Aβ, TNFα, Il-1β – suppress TrkB signaling and act via a common and novel mechanism. These factors all regulate the docking proteins (e.g., IRS and Shc) that link the activated Trk receptor to downstream effectors. While this is a novel mechanism underlying regulation of Trk signaling, such a mechanism has been identified for the insulin/IGF-1 receptor in the presence of proinflammatory cytokines and is one of the mechanisms for insulin/IGF-resistance, which is a key risk factor for type II diabetes (1). We suggest that accumulation of AB and proinflammatory cytokines during aging generates in the brain a “neurotrophin resistance” state that places the brain at risk for cognitive decline and dementia.     

Mechanisms of neuronal death in brain aging and Alzheimer's disease: role of endocrine-mediated calcium dyshomeostasis.

This paper reviews evidence that brain aging and Alzheimer's disease (AD) are somehow closely related and that the hippocampus (CA1) is highly vulnerable to cell loss under both conditions. In addition, two current lines of evidence on the mechanisms of hippocampal cell loss with aging are considered, including studies of neuronal calcium dysregulation and studies of cumulative glucocorticoid (GC) neurotoxicity. Moreover, recent electrophysiological studies have shown that excess glucocorticoid activation of hippocampal neurons increases the influx of calcium through voltage-activated calcium channels. Second messenger systems may mediate the steroid modulation of calcium channels. Therefore, it is hypothesized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer's disease.     

C-peptide and Central Nervous System Complications in Diabetes

Substantial evidence collected from clinical data and experimental studies has indicated that CNS is not spared from diabetes complications. Impairments in CNS function are well documented in both type 1 and type 2 diabetic patients as well as in various animal models of diabetes, in terms of alterations in cognition, neuropsychology, neurobehavior, electrophysiology, structure, neurochemistry and apoptotic activities. These data suggest that primary diabetic encephalopathy exists as a definable diabetic complication. The mechanisms underlying this CNS complication are not clear. Experimental studies have suggested that neuronal apoptosis may play an important role in neuronal loss and impaired cognitive function. In diabetes multiple factors are responsible for neuronal apoptosis, such as a perturbed IGF system, hyperglycemia and the aging process itself. Recent data suggest that insulin/C-peptide deficiency may exert an eminent role. Administration of C-peptide partially corrects the perturbed IGF system in the brain and prevents neuronal apoptosis in hippocampus of type 1 diabetes. In neuroblastoma SH-SY5Y cells C-peptide provides a dose-dependent stimulation on cell proliferation and an anti-apoptotic effect as well. These studies provide a basis for administration of C-peptide as a potentially effective therapy for type 1 diabetes.     

Cytogerontology at the beginning of the third millenium: from "correlative" to "gist" models

For the most part, research in the area of cytogerontology, i.e., investigation of the mechanisms of aging in the experiments on cultured cells, is carried out using the "Hayflick's model". More than forty years have passed since the appearance of that model, and during this period of time, very much data were obtained on its basis. These data contributed significantly to our knowledge of the behavior of both animal and human cultured cells. Specifically, we already know of the mechanisms underlying the aging in vitro. On the other hand, in my opinion, little has changed in our knowledge of the aging of the whole organism. In all likelihood, this can be explained by that the Hayflick's model is, like many others used in the experimental gerontology, correlative, i.e. based on a number of detected correlations. In the case of Hayflick's model, these are correlations between the mitotic potential of cells (cell population doubling potential) and some "gerontological" parameters and indices: species life-span, donor age, evidence of progeroid syndromes, etc., as well as various changes of normal (diploid) cells during long-term cultivation and during aging of the organism. It is, however, well known that very frequently a good correlation has nothing to do with the essence (gist) of the phenomenon. For example, we do know that the amount of gray hair correlates quite well with the age of an individual but is in no way related to the mechanisms of his/her aging and probability of death. In this case, the absence of cause-effect relationships is evident, which are, at the same time, indispensable for the development of gist models. These models, as distinct from the correlative ones, are based on a certain concept of aging. In the case of Hayflick's model, such a concept is absent: we cannot explain, using the "Hayflick's limit", why our organism ages. This conclusion was convincingly confirmed by the discovery of telomere mechanism which determines the aging of cells in vitro. That discovery initiated the appearance of theories attempting to explain the process of aging in vivo also on its basis. However, it has become clear that the mechanisms of aging of the entire organism, located, apparently, in its postmitotic cells, such as neurons or cardiomyocytes, cannot be explained in the framework of this approach. Hence, we believe that it is essential to develop "gist" models of aging using cultured cells. The mechanisms of cell aging in such models should be similar to the mechanisms of cell aging in the entire organism. Our "stationary phase aging" model could be one of such models, which is based on the assumption of the leading role of cell proliferation restriction in the processes of aging. We assume that the accumulation of "senile" damage is caused by the restriction of cell proliferation either due to the formation of differentiated cell populations during development (in vivo) or to the existence of saturation density phenomenon (in vitro). Cell proliferation changes themselves do not induce aging, they only lead to the accumulation of macromolecular defects, which, in turn, lead to the deterioration of tissues, organs, and, eventually, of the entire organism, increasing the probability of its death. Within the framework of our model, we define cell aging as the accumulation in a cell population of various types of damage identical to the damage arising in senescing multicellular organism. And, finally, it is essential to determine how the cell is dying and what the death of the cell is. These definitions will help to draw real parallels between the "genuine" aging of cells (i.e., increasing probability of their death with "age") and the aging of multicellular organisms.     

Luteinizing hormone: Evidence for direct action in the CNS

This article is part of a Special Issue “SBN 2014”.Hormonal dysfunction due to aging, especially during menopause, plays a substantial role in cognitive decline as well as the progression and development of neurodegenerative diseases. The hypothalamic–pituitary–gonadal (HPG) axis has long been implicated in changes in behavior and neuronal morphology. Most notably, estrogens have proven beneficial in the healthy brain through a host of different mechanisms. Recently, luteinizing hormone (LH) has emerged as a candidate for further investigation for its role in the CNS. The basis of this is that both LH and the LH receptor are expressed in the brain, and serum levels of LH correlate with cognitive deficits and Alzheimer's disease (AD) incidence. The study of LH in cognition and AD primarily focuses on evaluating the effects of downregulation of this peptide. This literature has shown that decreasing peripheral LH, through a variety of pharmacological interventions, reduces cognitive deficits in ovariectomy and AD models. However, few studies have researched the direct actions of LH on neurons and glial cells. Here we summarize the role of luteinizing hormone in modulating cognition, and we propose a mechanism that underlies a role for brain LH in this process.     

Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development

The establishment of functional neural circuits requires the guidance of axons in response to the actions of secreted and cell-surface molecules such as the semaphorins. Semaphorin 3E and its receptor PlexinD1 are expressed in the brain, but their functions are unknown. Here, we show that Sema3E/PlexinD1 signaling plays an important role in initial development of descending axon tracts in the forebrain. Early errors in axonal projections are reflected in behavioral deficits in Sema3E null mutant mice. Two distinct signaling mechanisms can be distinguished downstream of Sema3E. On corticofugal and striatonigral neurons expressing PlexinD1 but not Neuropilin-1, Sema3E acts as a repellent. In contrast, on subiculo-mammillary neurons coexpressing PlexinD1 and Neuropilin-1, Sema3E acts as an attractant. The extracellular domain of Neuropilin-1 is sufficient to convert repulsive signaling by PlexinD1 to attraction. Our data therefore reveal a "gating" function of neuropilins in semaphorin-plexin signaling during the assembly of forebrain neuronal circuits.     

Age-dependent remodelling of ionotropic signalling in cortical astroglia

Cortical astrocytes express fast ionotropic receptors for glutamate and ATP, although their role in neurone-glia communication remains controversial. Stimulation of neuronal afferents in mice neocortex triggers complex glial synaptic currents (GSCs) mediated by NMDA, P2X and AMPA receptors and glutamate transporters. In addition, astrocytes demonstrate spontaneous 'miniature' GSCs resulting from quantal release of neurotransmitters. Here, we demonstrate that maturation and aging of the brain of mice (from 1 to 21 months) affect the density of ionotropic receptors in astrocytes and their role in GSCs generation. The AMPA-receptor-mediated component is the largest in young animals and progressively declines with age. The P2X and NMDA components of GSC are smallest in young, maximal in adult (3 and 6 months old) and once more decrease in old mice, probably reflecting the remodelling of neuronal-glial circuitry. Our results demonstrate that fast synaptic transmission between neurones and astrocytes in neocortex that may be involved in information processing in neuronal-glial networks undergoes remodelling during brain maturation and aging.     

Astrocytes are a key conduit for upstream signaling of vasodilation during cerebral cortical neuronal activation in vivo

Astrocytes play an important role in the coupling between neuronal activity and brain blood flow via their capacity to "sense" neuronal activity and transmit that information to parenchymal arterioles. Here we show another role for astrocytes in neurovascular coupling: the ability to act as a signaling conduit for the vitally important process of upstream vasodilation (represented by pial arterioles) during both excessive (seizure) and physiological (sciatic nerve stimulation) increases in cerebral cortical neuronal activity. The predominance of an astrocytic rather than a vascular route was indicated by data showing that pial arteriolar-dilating responses to neuronal activation were completely blocked following selective disruption of the superficial glia limitans, whereas interference with interendothelial signaling was without effect. Results also revealed contributions from connexin 43, implying a role for gap junctions and/or hemichannels in the signaling process and that signaling from the glia limitans to pial arterioles may involve a diffusible mediator.     

Enhancement in Motor Learning through Genetic Manipulation of the Lynx1 Gene

The cholinergic system is a neuromodulatory neurotransmitter system involved in a variety of brain processes, including learning and memory, attention, and motor processes, among others. The influence of nicotinic acetylcholine receptors of the cholinergic system are moderated by lynx proteins, which are GPI-anchored membrane proteins forming tight associations with nicotinic receptors. Previous studies indicate lynx1 inhibits nicotinic receptor function and limits neuronal plasticity. We sought to investigate the mechanism of action of lynx1 on nicotinic receptor function, through the generation of lynx mouse models, expressing a soluble version of lynx and comparing results to the full length overexpression. Using rotarod as a test for motor learning, we found that expressing a secreted variant of lynx leads to motor learning enhancements whereas overexpression of full-length lynx had no effect. Further, adult lynx1KO mice demonstrated comparable motor learning enhancements as the soluble transgenic lines, whereas previously, aged lynx1KO mice showed performance augmentation only with nicotine treatment. From this we conclude the motor learning is more sensitive to loss of lynx function, and that the GPI anchor plays a role in the normal function of the lynx protein. In addition, our data suggests that the lynx gene plays a modulatory role in the brain during aging, and that a soluble version of lynx has potential as a tool for adjusting cholinergic-dependent plasticity and learning mechanisms in the brain.     

Mechanisms of neuronal death in brain aging and alzheimer's disease: Role of endocrine-mediated calcium dyshomeostasis

This paper reviews evidence that brain aging and Alzheimer's disease (AD) are somehow closely related and that the hippocampus (CA1) is highly vulnerable to cell loss under both conditions. In addition, two current lines of evidence on the mechanisms of hippocampal cell loss with aging are considered, including studies of neuronal calcium dysregulation and studies of cumulative glucocorticoid (GC) neurotoxicity. Moreover, recent electro-physiological studies have shown that excess glucocorticoid activation of hippocampal neurons increases the influx of calcium through voltage-activated calcium channels. Second messenger systems may mediate the steroid modulation of calcium channels. Therefore, it is hypothesized that excess glucocorticoid activation and neuronal calcium dysregulation may be two phases of a single process that increases the susceptibility of neurons to neurodegeneration during aging and Alzheimer's disease. © 1992 John Wiley & Sons, Inc.