scholarly journals Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Ashley M. Fortress ◽  
Mona Buhusi ◽  
Kris L. Helke ◽  
Ann-Charlotte E. Granholm
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Memory Impairments ◽  
Age Related ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Cholinergic Degeneration ◽  
And Function ◽  
Do So

Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the firstin vivoevidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

scholarly journals Neutrophils express the high affinity receptor for IgG (Fc gamma RI, CD64) after in vivo application of recombinant human granulocyte colony- stimulating factor

Blood ◽  
1991 ◽  
Vol 78 (4) ◽  
pp. 885-889 ◽  
Author(s):  
R Repp ◽  
T Valerius ◽  
A Sendler ◽  
M Gramatzki ◽  
H Iro ◽  
...  
Keyword(s):  
Fc Receptors ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
High Affinity ◽  
Healthy Donors ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Stimulating Factor

Abstract Fc receptors are important effector molecules of neutrophilic granulocytes (polymorphonuclear neutrophils [PMN]), connecting phagocytic cells and the specific immune response. Neutrophils from healthy donors express the low-affinity receptors for IgG Fc gamma RII (CD32) and Fc gamma RIII (CD16), but not the high-affinity receptor Fc gamma RI (CD64). The latter has been found on neutrophils from patients with certain bacterial infections and can be induced in vitro after incubation with interferon-gamma. We show here that neutrophils strongly express Fc gamma RI after in vivo application of recombinant human granulocyte colony-stimulating factor (rhG-CSF). PMN from patients receiving rhG-CSF displayed higher cytotoxicity against Daudi lymphoma cells in vitro compared with control patients and with healthy donors. Fab fragments against Fc gamma RII (monoclonal antibody [MoAb] IV.3) inhibited neutrophil-mediated cytotoxicity of healthy donors but not of patients during rhG-CSF therapy. Therefore, expression of Fc receptors by PMN was investigated by flow cytometry and the mean fluorescence intensity (MFI) was compared. After staining with MoAb 32.2 against Fc gamma RL, the median MFI of neutrophils from G-CSF patients (median, 4.78; range, 2.40 to 8.50; n = 5) was significantly higher (P = .002 and P = .001, respectively) than the median MFI of patients not receiving G-CSF (median, 1.23; range, 1.01 to 1.58; n = 6) and the median MFI of healthy donors (median, 1.04; range, 0.67 to 1.12; n = 6). Fc gamma RI disappeared after the discontinuing of the G- CSF injections, but was reinduced during the next treatment cycle with rhG-CSF. The high expression of Fc gamma RI during rhG-CSF therapy correlated with enhanced cytotoxicity. In vitro incubation with rhG-CSF also enhances cytotoxicity, but only minor increments in Fc gamma RI expression were observed. Thus, during in vivo application of rhG-CSF neutrophils acquire an additional potent receptor for mediating tumor cell killing in vitro by induction of the high-affinity receptor for IgG (Fc gamma RI, CD64).

scholarly journals Lsd1 prevents age-programed loss of beige adipocytes

2017 ◽  
Vol 114 (20) ◽  
pp. 5265-5270 ◽  
Author(s):  
Delphine Duteil ◽  
Milica Tosic ◽  
Dominica Willmann ◽  
Anastasia Georgiadi ◽  
Toufike Kanouni ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Fat Cell ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Age Related ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
And Function

Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Accordingly, adipocyte-specific increase of Lsd1 expression is sufficient to rescue the age-related transition of beige adipocytes to white adipocytes in vivo, whereas loss of Lsd1 precipitates it. Lsd1 maintains beige adipocytes by controlling the expression of peroxisome proliferator-activated receptor α (Ppara), and treatment with a Ppara agonist is sufficient to rescue the loss of beige adipocytes caused by Lsd1 ablation. In summary, our data provide insights into the mechanism controlling the age-related beige-to-white adipocyte transition and identify Lsd1 as a regulator of beige fat cell maintenance.

Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway

2008 ◽  
Vol 4 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Ying Y. Jean ◽  
Lauren D. Lercher ◽  
Cheryl F. Dreyfus
Keyword(s):  
Basal Forebrain ◽  
Metabotropic Glutamate Receptors ◽  
Cholinergic Neurons ◽  
Metabotropic Receptors ◽  
Western Blots ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Initial Work ◽  
Neuronal Signal ◽  
And Function

A key neurotrophin responsible for the survival and function of basal forebrain (BF) cholinergic neurons is brain-derived neurotrophic factor (BDNF). A number of studies now indicate that a source of this factor may be BF astrocytes. This study was designed to define the role of BF-astrocyte-derived BDNF on cholinergic neurons. Moreover, it investigated regulatory events that modulate BDNF content and release. In initial work BDNF derived from BF-astrocyte-conditioned medium (ACM) was found to increase both numbers of BF acetylcholinesterase (AChE+) cholinergic neurons and the cholinergic synthetic enzyme choline acetyltransferase (ChAT). Western blots, immunocytochemistry and pharmacological inhibition studies revealed that glutamate, through group I metabotropic glutamate receptors (mGluR), increases the intracellular levels of BDNF in BF astrocytes in culture, as well as its release. Furthermore, the release of BDNF is mediated by the actions of PLC, IP3 and internal stores of Ca2+. These results suggest that BF astrocytes serve as local sources of BDNF for cholinergic neurons, and that they may be regulated as such by the neuronal signal, glutamate, through the mediation of group I metabotropic receptors and the PLC pathway.

scholarly journals Somatostatin Presynaptically Inhibits Both GABA and Glutamate Release Onto Rat Basal Forebrain Cholinergic Neurons

2006 ◽  
Vol 96 (2) ◽  
pp. 686-694 ◽  
Author(s):  
Toshihiko Momiyama ◽  
Laszlo Zaborszky
Keyword(s):  
Basal Forebrain ◽  
Glutamate Release ◽  
Cholinergic Neurons ◽  
External Solution ◽  
Amplitude Distribution ◽  
Receptor Subtype ◽  
Whole Cell Patch Clamp ◽  
Bath Application ◽  
Presynaptic Currents

A whole cell patch-clamp study was carried out in slices obtained from young rat brain to elucidate the roles of somatostatin in the modulation of synaptic transmission onto cholinergic neurons in the basal forebrain (BF), a region that contains cholinergic and GABAergic corticopetal neurons and somatostatin (SS)-containing local circuit neurons. Cholinergic neurons within the BF were identified by in vivo prelabeling with Cy3 IgG. Because in many cases SS is contained in GABAergic neurons in the CNS, we investigated whether exogenously applied SS can influence GABAergic transmission onto cholinergic neurons. Bath application of somatostatin (1 μM) reduced the amplitude of the evoked GABAergic inhibitory presynaptic currents (IPSCs) in cholinergic neurons. SS also reduced the frequency of miniature IPSCs (mIPSCs) without affecting their amplitude distribution. SS-induced effect on the mIPSC frequency was significantly larger in the solution containing 7.2 mM Ca2+ than in the standard (2.4 mM Ca2+) external solution. Similar effects were observed in the case of non-NMDA glutamatergic excitatory postsynaptic currents (EPSCs). SS inhibited the amplitude of evoked EPSCs and reduced the frequency of miniature EPSCs dependent on the external Ca2+ concentration with no effect on their amplitude distribution. Pharmacological analyses using SS-receptor subtype–specific drugs suggest that SS-induced action of the IPSCs is mediated mostly by the sst2 subtype, whereas sst subtypes mediating SS-induced inhibition of EPSCs are mainly sst1 or sst4. These findings suggest that SS presynaptically inhibits both GABA and glutamate release onto BF cholinergic neurons in a Ca2+-dependent way, and that SS-induced effect on IPSCs and EPSCs are mediated by different sst subtypes.

Sema4D induces angiogenesis through Met recruitment by Plexin B1

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4321-4329 ◽  
Author(s):  
Paolo Conrotto ◽  
Donatella Valdembri ◽  
Simona Corso ◽  
Guido Serini ◽  
Luca Tamagnone ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Large Family ◽  
Transmembrane Receptors ◽  
Biologic Effects ◽  
High Affinity Receptor ◽  
Membrane Bound ◽  
Affinity Receptor ◽  
Developing Nervous System

Abstract Semaphorins, a large family of membrane-bound and secreted proteins, signal through their transmembrane receptors, the plexins. Semaphorins and plexins share structural homologies with scatter factor receptors, a family of tyrosine kinase receptors for which Met is the prototype. Semaphorins have been studied primarily in the developing nervous system, where they act as repelling cues in axon guidance. However, they are widely expressed in several tissues, and their role in epithelial morphogenesis has been recently established. Not much is known about their role in angiogenesis, a key step during embryonic development and adulthood. Here we demonstrate that a semaphorin, Sema4D, is angiogenic in vitro and in vivo and that this effect is mediated by its high-affinity receptor, Plexin B1. Moreover, we prove that biologic effects elicited by Plexin B1 require coupling and activation of the Met tyrosine kinase. In sum, we identify a proangiogenic semaphorin and provide insight about the signaling machinery exploited by Plexin B1 to control angiogenesis.

scholarly journals Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

2009 ◽  
Vol 102 (4) ◽  
pp. 2194-2207 ◽  
Author(s):  
David Murchison ◽  
Angelika N. McDermott ◽  
Candi L. LaSarge ◽  
Kathryn A. Peebles ◽  
Jennifer L. Bizon ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Cognitive Status ◽  
Cognitively Impaired ◽  
Aged Rats ◽  
Middle Aged ◽  
Cholinergic Basal Forebrain ◽  
Age Related ◽  
Forebrain Neurons ◽  
Firing Properties

Alterations in neuronal Ca2+ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca2+ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca2+ current recording with Ca2+-sensitive ratiometric microfluorimetry to measure Ca2+ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age- or cognition-related changes in the amplitudes or fractional compositions of the whole cell Ca2+ channel currents. However, Ca2+ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca2+ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca2+ buffering by cholinergic basal forebrain neurons may be important during aging.

scholarly journals Atrophy of Basal Forebrain Initiates with Tau Pathology in Individuals at Risk for Alzheimer’s Disease

2019 ◽  
Vol 30 (4) ◽  
pp. 2083-2098
Author(s):  
Jose L Cantero ◽  
Mercedes Atienza ◽  
Carmen Lage ◽  
Laszlo Zaborszky ◽  
Eduard Vilaplana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Nucleus Basalis ◽  
Tau Pathology ◽  
Projection System ◽  
Prodromal Ad

Abstract Evidence suggests that the basal forebrain (BF) cholinergic system degenerates early in the course of Alzheimer’s disease (AD), likely due to the vulnerability of BF cholinergic neurons to tau pathology. However, it remains unclear whether the presence of tauopathy is the only requirement for initiating the BF degeneration in asymptomatic subjects at risk for AD (AR-AD), and how BF structural deficits evolve from normal aging to preclinical and prodromal AD. Here, we provide human in vivo magnetic resonance imaging evidence supporting that abnormal cerebrospinal fluid levels of phosphorylated tau (T+) are selectively associated with bilateral volume loss of the nucleus basalis of Meynert (nbM, Ch4) in AR-AD individuals. Spreading of atrophy to medial septum and vertical limb of diagonal band Broca (Ch1–Ch2) occurred in both preclinical and prodromal AD. With the exception of A+, all groups revealed significant correlations between volume reduction of BF cholinergic compartments and atrophy of their innervated regions. Overall, these results support the central role played by tauopathy in instigating the nbM degeneration in AR-AD individuals and the necessary coexistence of both AD proteinopathies for spreading damage to larger BF territories, thus affecting the core of the BF cholinergic projection system.

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