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At least 1,099 records · Page 61Linked to original sources
PubMed2004

A new Alzheimer's disease interventive strategy: GLP-1.

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.

Alzheimer Disease↗
PubMed1993

A quantitative study of the perikaryon and the basal dendritic tree in rat hippocampus (CA1) pyramids following different experimental procedures.

A quantitative study of perikaryon and basal dendritic branching of hippocampal (CA1) neurons in male Wistar rats, in three experimental groups is reported. The groups of animals were exposed to treatment with either a tricyclic antidepressant, or a saline control injection or no handling. The hippocampal tissue was studied following Golgi-Kopsch impregnation and comparative measurements made using semi-automatic image analysis and light microscopy. Measurements of the extent of basal dendritic branching showed a significant difference (p < 0.01) between the saline-injected and unhandled control groups. The drug-injected and saline-injected groups had similar values although the drug-injected group did not prove to be significantly different from the unhandled controls. No statistical difference was noted in the perikaryon size of the three experimental groups. These results are discussed with reference to the effects of sensory stimulation on neuronal plasticity.

Animals↗
PubMed1991

[Brain development and gonadal hormones].

Gonadal steroids play an important role in exerting functional sexual differentiation of the brain. Recently there has been accumulating evidence that gonadal steroids regulate neuron number, axonal and dendritic growth and synapse formation in the neuronal system containing sex steroid receptors. These provide morphological bases for sexually dimorphic function of the brain. Other than in the developmental process, gonadal steroids are found to take care of neuronal plasticity in certain brain areas.

Androgens↗
PubMed2005

Neonatal seizures: to treat or not to treat?

The immature brain is intrinsically hyperexcitable, a feature that, despite being crucial for learning, synaptogenesis and neuronal plasticity, predisposes the neonate to seizures. Seizures represent the most common neurologic manifestation of impaired brain function in this age group. Importantly, although seizure-induced neuronal injury is minimal in the "healthy" neonatal brain, the "metabolically-compromised" brain appears more vulnerable. Even in the "healthy" brain, however, seizures result in impaired learning, enhanced susceptibility to further seizures, and increased risk of brain injury with seizures later in life, as a result of altered hippocampal circuitry. Given these findings, an aggressive approach to neonatal seizures appears warranted. However, our current conventional therapies (including phenobarbital, phenytoin, and benzodiazepines), even when used in combination, are often ineffective in controlling seizures. Lidocaine may yield better efficacy but requires more study. Recent animal data suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists such as topiramate may have a neuroprotective role. However, further work is needed to confirm the safety of excitatory amino acid antagonists in neonates because there remains a prevailing concern that such agents may impair normal neurodevelopmental processes.

Animals↗
PubMed1994

K(+)- and transmitter-induced rises in [Ca2+]i in auditory neurones of developing rats.

Ca2+ ions are thought to play important roles in processes underlying neuronal plasticity such as synapse stabilization. We employed the Fura-2 technique on brainstem slices of neonatal rats to measure changes in intracellular Ca2+ ([Ca2+]i) in neurons of the lateral superior olive (LSO) in order to analyse whether these cells have functional Ca2+ channels when synaptic maturation takes place. Rises in intracellular Ca2+ could be induced by KCl-evoked depolarizations or by glutamate, but not by glycine or GABA. These results show that Ca2+ channels are present in developing LSO neurones and that many of them, if not all, belong to the voltage-sensitive type. We speculate that these channels play a role during ontogeny by mediating Ca(2+)-dependent mechanisms of synapse stabilization.

Aging↗
PubMed2002

Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent.

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase expressed in the CNS during events that require neuronal plasticity. In this study we demonstrate that endogenous tPA mediates the progression of kainic acid-induced (KA-induced) seizures by promoting the synchronization of neuronal activity required for seizure spreading, and that, unlike KA-induced cell death, this activity is plasminogen-independent. Specifically, seizure induction by KA injection into the amygdala induces tPA activity and cell death in both hippocampi, and unilateral treatment of rats with neuroserpin, a natural inhibitor of tPA in the brain, enhances neuronal survival in both hippocampi. Inhibition of tPA within the hippocampus by neuroserpin treatment does not prevent seizure onset but instead markedly delays the progression of seizure activity in both rats and wild-type mice. In tPA-deficient mice, seizure progression is significantly delayed, and neuroserpin treatment does not further delay seizure spreading. In contrast, plasminogen-deficient mice show a pattern of seizure spreading and a response to neuroserpin that is similar to that of wild-type animals. These findings indicate that tPA acts on a substrate other than plasminogen and that the effects of neuroserpin on seizure progression and neuronal cell survival are mediated through the inhibition of tPA.

Amygdala↗
PubMedDate not supplied

Plasticity in Alzheimer's disease: too much or not enough?

The goal of optimizing restorative sprouting in Alzheimer's disease is based on the premise that sprouting is beneficial and is deficient in AD. The beneficial aspects of neuronal plasticity have been questioned, however, and other studies suggest that some aspects of sprouting may be exaggerated in AD and contribute to the formation of plaques, tangles, and other neuropathological hallmarks of this disorder. Manipulation of the sprouting response may represent a promising treatment strategy in AD, but whether the goal is to augment or impede sprouting may depend upon the extent of the damage and the severity of the disease state.

Aged↗
PubMed2007

DNA damage responses in neural cells: Focus on the telomere.

Postmitotic neurons must survive for the entire life of the organism and be able to respond adaptively to adverse conditions of oxidative and genotoxic stress. Unrepaired DNA damage can trigger apoptosis of neurons which is typically mediated by the ataxia telangiectasia mutated (ATM)-p53 pathway. As in all mammalian cells, telomeres in neurons consist of TTAGGG DNA repeats and several associated proteins that form a nucleoprotein complex that prevents chromosome ends from being recognized as double strand breaks. Proteins that stabilize telomeres include TRF1 and TRF2, and proteins known to play important roles in DNA damage responses and DNA repair including ATM, Werner and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). We have been performing studies of developing and adult neurons aimed at understanding the effects of global and telomere-directed DNA damage responses in neuronal plasticity and survival in the contexts of aging and neurodegenerative disorders. Deficits in specific DNA repair proteins, including DNA-PKcs and uracil DNA glycosylase (UDG), render neurons vulnerable to adverse conditions of relevance to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and stroke. Similarly, early postmitotic neurons with reduced telomerase activity exhibit accentuated responses to DNA damage and are prone to apoptosis demonstrating a pivotal role for telomere maintenance in both mitotic cells and postmitotic neurons. Our recent findings suggest key roles for TRF2 in regulating the differentiation and survival of neurons. TRF2 affects cell survival and differentiation by modulating DNA damage pathways, and gene expression. A better understanding of the molecular mechanisms by which neurons respond to global and telomere-specific DNA damage may reveal novel strategies for prevention and treatment of neurodegenerative disorders. Indeed, work in this and other laboratories has shown that dietary folic acid can protect neurons against Alzheimer's disease by keeping homocysteine levels low and thereby minimizing the misincorporation of uracil into DNA in neurons.

Animals↗
PubMed1990

Immortalization of bipotential and plastic glio-neuronal precursor cells.

Permanent clonal cell lines from newborn mouse striatum have been established after transfer of the simian virus 40 large tumor oncogene by means of a retroviral vector. Some of the lines obtained displayed properties of bipotential and plastic glio-neuronal precursors. Depending on the culture conditions, these cells express either the glial fibrillary acidic protein or neurofilaments. In addition, the cells can display adrenergic, D1 and D2 dopaminergic, muscarinic, and 5-hydroxytryptamine type 2 serotoninergic receptors, which are coupled either to the adenylate cyclase or to the phosphatidylinositol signaling pathways. The panel of receptors for neurotransmitters exhibited by these lines closely resembles that of primary striatal neurons. Results suggest that plastic common precursors of astrocytes and neurons persist in the striatum at a late developmental stage. As these permanent cell lines constitute an unlimited source of homogenous cell material, we suggest that they should be useful for molecular and pharmacological studies on the mechanisms and regulation of signal transduction as well as the commitment, plasticity, and differentiation of neural cells.

Animals↗
PubMed1996

Autonomic nervous system as a model of neuronal aging: the role of target tissues and neurotrophic factors.

The aim of this study was to determine the role of target tissues and neurotrophic factors in the growth and atrophy of autonomic neurons during development and aging. Using quantitative neuroanatomical techniques, it is shown that, although axonal and dendritic growth is apparent throughout postnatal development, different patterns of growth are found in autonomic neurons innervating different target tissues. For example, sympathetic neurons innervating the submandibular gland continue to grow well into maturity, but those innervating the iris cease net growth early in postnatal development. Similarly, although neuronal atrophy was observed in aged autonomic ganglia, this was not a general phenomenon but was specific to neurons innervating particular target tissues. Sympathetic neurons innervating the middle cerebral artery showed significant axonal and dendritic atrophy in old age, whereas neurons innervating the iris were morphologically unchanged. The trophic influence of peripheral target tissues on their innervating neurons has been shown to decline in old age possibly as a result of decreased availability of target-derived neurotrophic factors such as nerve growth factor (NGF) [Gavazzi et al. (1992) Neuroreport, 3:717-720]. Therefore, in an attempt to reverse neuronal atrophy where it occurred, NGF was infused via miniosmotic pumps over the peripheral axons of aged neurons. NGF induced increases in soma size, dendritic length and axonal arborization. However, in contrast to young adult neurons, no increase in the number of dendritic branch points or primary dendrites was observed, suggesting that some aspects of neuronal plasticity are impaired in old age. In sum, these results show a range of age- and target-specific differences in the axonal and dendritic morphology of autonomic neurons that may result from differing trophic interactions with their target tissues.

Aging↗
PubMed2004

Alpha-synuclein and Parkinson's disease.

Alpha-synuclein (alpha-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. Interest in alpha-syn has increased dramatically after the discovery of a relationship between its dysfunction and several neurodegenerative diseases, including Parkinson's disease (PD). The physiological functions of alpha-syn remain to be fully defined, although recent data suggest a role in regulating membrane stability and neuronal plasticity. Various trigger factors, either environmental or genetic, can lead to a cascade of events involving misfolding or loss of normal function of alpha-syn. In dopaminergic neurons, this may promote a vicious cycle in which elevation in cytoplasmic dopamine, oxidative stress, alpha-syn dysfunction, and disruption of vesicle function lead to dopaminergic cell loss and PD. Alpha-syn dysfunction appears to be a common feature of all forms of PD. The mechanism by which alpha-syn induces neuronal cell toxicity may invoke multiple pathways, such as aggregation or interaction with other proteins and molecules, including synphilin-1, chaperone 14-3-3 protein, and dopamine itself. This complexity has hindered the development of models to study PD. The available animal models of PD, each present distinct advantages and limits. Findings to date suggest that alpha-syn-based models represent a paradigm, which is closest to the human pathology.

Amino Acid Sequence↗
PubMed1988

Neuronal maintenance and neurite extension of adult mouse neurones in non-neuronal cell-reduced cultures is dependent on substratum coating.

Adult mouse DRG neurones have been maintained for 14 days in cultures where non-neuronal cell proliferation was inhibited by the inclusion of 5 x 10(-6) microM-cytosine arabinoside (AraC) in the medium from the onset of culture. On uncoated plastic neurone numbers significantly declined in the absence of non-neuronal cell outgrowth compared with uninhibited co-cultures. However, when neurones were maintained in the presence of AraC on certain coated surfaces this decrease in neurone numbers was not observed. Combinations of fibronectin (FN) and laminin (LAM) proved most effective for 7 and 14 days in vitro, although either was beneficial if used separately. Microexudates produced by the fibroblast line, 3T6, also significantly improved neuronal counts for 14 days in vitro. However, a microexudate derived from primary cultures of mouse hepatocytes, although advantageous for 7 days in vitro, was not effective in maintaining neurones over the 14-day culture period, reminiscent of previous observations when synthetic cationic agents were used. Electrophoretic analysis of the fibroblast exudate indicated that fibronectin was present in the substrate-attached material generated by this cell line. The reduction in non-neuronal cell growth facilitated the monitoring of neuronal structural detail by scanning electron microscopy. Examination of neurite extension, indicative of neurone differentiation, was particularly improved. FN/LAM and the fibroblast-derived exudate increased nerve fibre growth, whilst the hepatocyte exudate had little effect on neurite regeneration, and polylysine had a detrimental effect. The data demonstrate that substrata can have a significant effect on maintenance and differentiation of adult neurones in primary culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Survival signaling pathways activated by NMDA receptors.

N-methyl-D-aspartate receptors (NMDAR) have a recognized role in neuronal plasticity while their excessive activation results in excitotoxic death. Therefore, NMDAR antagonists are considered for neuroprotective interventions. However, there is also an emerging role of NMDAR in supporting neuronal survival. Thus, during CNS development, basal NMDAR activity suppresses neuronal apoptosis while moderate NMDAR activation may, at least under some conditions, protect against excitotoxic/ischemic insults. These suggest that while protecting from excitotoxicity, NMDAR antagonists would also reduce pro-survival activity of NMDAR. Hence, the identification of the switches controlling pro-survival vs. pro-excitotoxic outcome of NMDAR stimulation may lead to development of NMDAR antagonists that selectively block the excitotoxicity while enhancing the protective NMDAR signaling. On the other hand, the existence of anti-apoptotic/pro-proliferative NMDAR signaling in transformed cells may result in new strategies to attack cancer. This review focuses on the emerging field of neuroprotective signaling mediators that are implicated in pro-survival activity of NMDAR. We discuss the evidence implicating either NR2B or nonNR2B NMDAR in mediating the protection. We also present the reports linking NMDAR-mediated protection to the activation of survival signaling kinases including ERK and Akt, or suppression of a pro-apoptotic kinase, GSK-3beta. The protective role of transcription factors is also discussed. Finally, we review the existing evidence suggesting that NMDAR support survival by regulating the pro-survival trophic factor signaling and/or the cell death machinery. Although NMDAR provide a major survival input to CNS neurons, the NMDAR-activated protective signaling is poorly understood and, therefore, deserves further research effort.

Animals↗
PubMed1983

Development of cholinergic sympathetic neurons: evidence for transmitter plasticity in vivo.

Most principal neurons in sympathetic ganglia are noradrenergic. A small population, especially those that innervate sweat glands in rat footpads, are cholinergic. We have characterized the innervation of the glands in adult and developing rats to determine whether sympathetic neurons undergo a transition from noradrenergic to cholinergic during normal development as has been observed in culture. In adult rats, the fibers innervating sweat glands exhibited strong acetylcholinesterase (AChE) staining and vasoactive intestinal peptide (VIP)-like immunoreactivity. None of the axons contained endogenous catecholamines detectable with formaldehyde-induced fluorescence or permanganate fixation. However, like cholinergic sympathetic neurons in culture, all axons could take up and store exogenous catecholamine. The sweat glands and their innervation develop postnatally. At 7 days, the axons innervating sweat glands possessed endogenous catecholamine histofluorescence and small granular vesicles but not AChE or VIP. By 14 days, AChE and VIP staining was pronounced. In contrast, catecholamine fluorescence and the number of small granular vesicles were reduced, and by 21 days they were absent. Further, neonatal treatment with 6-hydroxydopamine, a toxic norepinephrine congener, resulted in the loss of cholinergic as well as noradrenergic sympathetic innervation. These observations are consistent with a transition from noradrenergic to cholinergic function in vivo.

Acetylcholine↗
PubMed1993

Loss of 5-HT1A receptor mRNA in the dentate gyrus of the long-term adrenalectomized rats and rapid reversal by dexamethasone.

Two months after bilateral adrenalectomy, 5-HT1A receptor mRNA labelling was decreased in the granular cell layer of the dentate gyrus but not in the pyramidal cell layer of Ammon's horn. Two month adrenalectomized rats given dexamethasone (10 micrograms/ml saline) 24 or 72 h before perfusion showed a progressive recovery in 5-HT1A mRNA labelling in the dentate gyrus. 5-HT1A expression may underlie hippocampal neuronal plasticity after long-term adrenalectomy.

Adrenalectomy↗
PubMed1994

Glutamate receptor modulation by protein phosphorylation.

Glutamate-gated ion channels mediate most excitatory synaptic transmission in the mammalian central nervous system and play major roles in synaptic plasticity, neuronal development, and in some neuropathological conditions. Recent studies have suggested that protein phosphorylation of neuronal glutamate receptors by cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) may regulate their function and play a role in some forms of synaptic plasticity. To test whether these protein kinase effects are due to direct phosphorylation of the receptors and to further examine the sites and mechanisms by which the receptors are modulated, we transiently expressed recombinant glutamate receptors in HEK-293 cells and studied their biochemical and biophysical properties. Our results indicate that the kainate-preferring receptor GluR6 is phosphorylated by PKA, primarily on a single serine in the proposed major intracellular loop. Moreover, using the whole cell patch clamp recording technique, we have shown that phosphorylation at this site increases the amplitude of the GluR6-mediated glutamate current without significantly altering its dose-response, current-voltage relation or desensitization kinetics. In other experiments, we have demonstrated that the NMDA receptor subunit NR1 is phosphorylated by PKC on several distinct sites, and most of these sites are located within a single alternatively spliced exon in the C-terminal domain. These findings suggest that RNA splicing can regulate NMDA receptor phosphorylation and that, contrary to the previously proposed membrane topology model, the NR1 C-terminus is intracellular. Furthermore, in HEK-293 cells co-transfected with NR2A and NR1 subunits containing the C-terminal exon with the PKC phosphorylation sites, our preliminary studies indicate that the NMDA-evoked current is potentiated by intracellular PKC. We are currently examining PKC effects on the NMDA-evoked current responses of mutant NR1 receptors that lack the C-terminal phosphorylation sites. These studies provide evidence that glutamate receptors are directly phosphorylated and functionally modulated by protein kinases. Moreover, by identifying phosphorylation sites within the receptor proteins, our results provide information about the structure and membrane topology of these receptors.

Animals↗
PubMed1992

Excitatory amino acids and memory: evidence from research on Alzheimer's disease and behavioral pharmacology.

The excitatory amino acid transmitter (EAA) system is believed to play a crucial role in a variety of physiological processes related to neuronal plasticity. Substantial neurophysiological evidence suggests that, under normal physiological conditions. EAAs may be involved in mechanisms underlying learning and memory. However, overactivity of this system produces excitotoxic damage to neurons which is believed to be an etiological factor in various neurological conditions, such as epilepsy, and stroke-induced impairments. The fact that EAAs have been implicated in both, normal cognitive function and in degenerative neurological conditions suggests that they may contribute to the etiology of Alzheimer's disease (AD), because AD is characterized by memory deficits and specific histopathological signs of neuronal damage. This paper summarizes information regarding 1) the involvement of EAAs in Alzheimer's disease and 2) results from psychopharmacological studies of EAAs in laboratory animal models of learning. Investigations of the pathophysiology of AD indicate that glutamatergic deficits are associated with this syndrome. However, there is controversy concerning the nature of this defect. As a result, it is unclear whether it is a consequence of excitotoxic changes produced by glutamatergic overactivity or result from a decrease in glutamatergic function. Evidence from behavioral studies is consistent with the conclusion that EAAs may be involved in the acquisition of conditioned responses. However, in parallel with the clinical findings, learning impairments have been produced by treatments which either increase or decrease activity within this transmitter system. Therefore, although present results suggest that the EAAs play a role in cognition and in clinical syndromes in which such function is compromised, the specific nature of that role needs to be elucidated by future research.

Alzheimer Disease↗
PubMed1998

Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity.

Oxyradicals attack double bonds of unsaturated fatty acids in cell membranes in a process called membrane lipid peroxidation (MLP).This process occurs in many different acute and chronic neurodegenerative conditions, and to a lesser extent during normal physiological activity in neuronal circuits. It can modify neurotransmitter release and uptake, ion-channel activity, the function of ion-motive ATPases and glucose transporters,and the coupling of cell-surface receptors to GTP-binding proteins. MLP can also impair mitochondrial function and promote a cascade of events that culminates in apoptotic cell death. The lipid peroxidation product 4-hydroxynonenal might play a central role in MLP-induced alterations in plasma membrane and mitochondrial protein functions. The modification of processes such as outgrowth of neurites and long-term potentiation of synaptic transmission by agents that suppress or promote MLP suggests roles for subtoxic levels of MLP in neuronal plasticity.

Adaptation, Physiological↗