Neuritin, also known as CPG15, is a neurotrophic factor that was initially discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin plays multiple roles in the process of neural development and synaptic plasticity, although its binding receptor(s) and downstream signaling effectors remain unclear. In this study, we found that the cortical and hippocampal expression of neuritin is reduced in the brains of Alzheimer's disease (AD) patients and demonstrated that viral-mediated expression of neuritin in the dentate gyrus of 13-month-old Tg2576 mice, an AD animal model, attenuated a deficit in learning and memory as assessed by a Morris water maze test. We also found that neuritin restored the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neuron cultures prepared from Tg2576 mice. It was also shown that viral-mediated expression of neuritin in the dentate gyrus of 7-week-old Sprague-Dawley rats increased neurogenesis in the hippocampus. Taken together, our results demonstrate that neuritin restores the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neurons from Tg2576 neurons, and also attenuates cognitive function deficits in Tg2576 mouse model of AD, suggesting that neuritin possesses a therapeutic potential for AD.
There is growing evidence that inflammatory processes of activated microglia could play an important role in the progression of nerve cell damage in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease which harbor features of chronic microglial activation, though the precise mechanism is unknown. In this study, we presented in vivo and ex vivo experimental evidences indicating that activated microglia could exacerbate the survival of axotomized dopaminergic neurons and that appropriate inactivation of microglia could be neuroprotective.
The transection of medial forebrain bundle (MFB) of a rat induced loss of dopaminergic neurons in a time-dependent manner and accompanied with microglial activation. Along with microglial activation, production of reactive oxygen species (ROS) was upregulated and TH/OX6/hydroethidine triple-immunofluorescence showed that the microglia mainly produced ROS. When the activated microglial cells that were isolated from the substantia nigra of the MFB axotomized animal, were transplanted into the substantia nigra of which MFB had been transected at 7 days ago, the survival rate of axotomized dopaminergic neurons was significantly reduced as compared with sham control. Meanwhile, when the microglial activation was attenuated by administration of tuftsin fragment 1-3 (microglia inhibitory factor) into the lateral ventricle using mini-osmotic pump, the survival rate of axotomized dopaminergic neurons was increased.
The present study suggests that activated microglia could actively produce and secrete unfavorable toxic substances, such as ROS, which could accelerate dopaminergic neuronal cell loss. So, well-controlled blockade of microglial activation might be neuroprotective in some neuropathological conditions.
Medial forebrain bundle (MFB); Axotomy; Activated microglia; Reactive oxygen species; Tuftsin fragment 1-3
ErbB4has emerged as a leading susceptibility gene for schizophrenia but the function of the ErbB4 receptor in the adult brain is unknown. Here we show in the adult hippocampus that long-term potentiation (LTP) of transmission at Schaffer-collateral CA1 synapses was markedly enhanced in mutant mice lacking ErbB4. Concordantly, LTP was enhanced by acutely blocking ErbB4 in wild type animals, indicating that ErbB4 activity constitutively suppresses LTP. Moreover, increasing ErbB4 signaling further suppressed LTP. By contrast, altering ErbB4 activity did not affect basal synaptic transmission or short-term facilitation. Our findings suggest that cognitive deficits in schizophrenia may be a consequence of hyperfunction of ErbB4 signaling leading to suppressed glutamatergic synaptic plasticity, thus opening new approaches for treatment of this disorder.
PMID: 18185097 CAMSID: cams2735
ErbB4; transgenic mouse; neuregulin; Schaffer collateral-CA1 synapses; long-term potentiation; theta burst stimulation; synaptic plasticity; paired-pulse facilitation
Apoptosis inducing factor (AIF) has been proposed to act as a putative reactive oxygen species scavenger in mitochondria. When apoptotic cell death is triggered, AIF translocates to the nucleus, where it leads to nuclear chromatin condensation and large-scale DNA fragmentation which result in caspase-independent neuronal death. We performed this study to investigate the possibility that, in addition to caspase-dependent neuronal death, AIF induced neuronal death could be a cause of neuronal death in Alzheimer's disease (AD). We have found that AIF immunoreactivity was increased in the hippocampal pyramidal neurons in the Alzheimer brains compared to those of healthy, age-matched control brains. Nuclear AIF immunoreactivity was detected in the apoptotic pyramidal CA1 neurons at the early stage of AD and CA2 at the advanced stage. Nuclear AIF positive neurons were also observed in the amygdala and cholinergic neurons of the basal forebrain (BFCN) from the early stages of AD. The results of this study imply that AIF-induced apoptosis may contribute to neuronal death within the hippocampus, amygdala, and BFCN in early of AD.
Alzheimer disease; Apoptosis inducing factor; Caspase-independent neuronal death; Human brain
Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and has also been reported to exhibit potent neuroprotective properties. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its role in Alzheimer's disease (AD). AD is characterized by progressive impairment of cognition and behavioral disturbance that strongly correlate with degeneration and death of neurons in the cerebral cortex and limbic brain areas, such as the hippocampus and the amygdala. Here, we show that the ErbB4 and phospho-ErbB4 immunoreactivities were higher intensity in the neurons of the CA1-2 transitional field of AD brains as compared to age-matched controls. Also, ErbB4 expression was increased in the neurons of the cortico medial nucleus amygdala, human basal forebrain and superior frontal gyrus of AD brains. In cerebral cortex and hippocampus of amyloid precursor protein/presenilin 1 double transgenic mice, ErbB4 immunoreactivity significantly increased in comparison to age-matched wild type control. These results suggest that up-regulating of ErbB4 immunoreactivity may involve in the progression of pathology of AD.
Alzheimer disease; ErbB4 receptor; Limbic structures; Neurodegeneration
Neuregulin-1 (NRG1) signaling participates in the synaptic plasticity, maintenance or regulation of adult brain. Although ErbB4, a key NRG1 receptor, is expressed in multiple regions in the adult animal brain, little is known about its localization in Alzheimer's disease (AD) brains. We previously reported that ErbB4 immunoreactivity showed regional difference in the hippocampus of age-matched control. In the present paper, immunohistochemical characterization of the distribution of ErbB4 receptor in the hippocampus relative to pathology staging were performed in age-matched control (Braak stage 0, n=6) and AD (Braak stage I/V, n=10). Here, we found that ErbB4 immunoreactivity was significantly increased in apoptotic hippocampal pyramidal neurons in the brains of AD patients, compared to those of age-matched control subjects. In AD brains, ErbB4 immunoreactivity was demonstrated to colocalize with the apoptotic signal Bax in apoptotic hippocampal pyramidal neurons. These results suggest that up-regulation of ErbB4 immunoreactivity in apoptotic neuron may involve in the progression of pathology of AD.
Alzheimer's disease; ErbB4 receptor; Bax; Apoptosis; Neurodegeneration
Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.
Amyloid precursor protein binding protein-1; Amyloid precursor protein; Alzheimer's disease; cell cycle; Tg2576 mice
Neuregulin-1 (NRG1) plays an important role in neural development, synapse formation and synaptic plasticity by activating ErbB receptor tyrosine kinases. Although ligand-induced endocytosis has been shown to be important for many receptor tyrosine kinases, whether NRG1 signaling depends on ErbB endocytosis remains controversial. Here we provide evidence that ErbB4, a prominent ErbB protein in the brain, becomes internalized in NRG1-stimulated neurons. The induced ErbB4 endocytosis requires its kinase activity. Remarkably, inhibition of ErbB endocytosis attenuates NRG1-induced activation of Erk and Akt in nuerons. These observations indicate a role of ErbB endocytosis in NRG1 signaling in neurons.
ErbB4; tyrosine kinase; neuregulin; internalization; endocytosis; biotinylation; neurons; schizophrenia
Neuregulin1 (NRG1) has been strongly linked genetically to schizophrenia although the pathophysiological role it plays in the disease is not known. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse as well as defects in early development of the hippocampal – cortical circuitry. Here we show that erbB4, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/ErbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link NRG1/erB4 function to the major models proposed for the etiology of schizophrenia.
The mechanism of stimulation of noradrenaline (NA) release by nicotine (NIC) was investigated in human cerebral cortex slices preloaded with [3H]-noradrenaline.NIC (10–1000 μM) increased [3H]-NA release in a concentration-dependent manner.NIC (100 μM)-evoked [3H]-NA release was largely dependent on external Ca2+, and was attenuated by ω-conotoxin GVIA (0.1 μM) but not by nitrendipine (1 μM).Tetrodotoxin (1 μM) and nisoxetine (0.1 μM) attenuated the NIC (100 μM)-evoked release of [3H]-NA.Mecamylamine (10 μM), dihydro-β-erythroidine (10 μM) and d-tubocurarine (30 μM), but not α-bungarotoxin (α-BTX, 0.1 μM), attenuated the NIC (100 μM)-evoked release of [3H]-NA.NIC (100 μM)-evoked release of [3H]-NA was not affected by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 30 μM) and D(−)-2-amino-5-phosphonopentanoic acid (D-AP5, 100 μM), but attenuated by MK-801 (10 μM). MK-801 (0.1–1000 μM) displaced the specific binding of [3H]-nisoxetine with Ki values of 91.2 μM. NIC (100, 300 and 1000 μM) did not induce [3H]-D-aspartate release in human cerebral cortex slices.NIC (100 μM)-evoked release of [3H]-NA was attenuated by 7-nitroindazole (10 μM), NG-nitro-L-arginine methyl ester HCl (L-NAME, 30 μM), NG-monomethyl-L-arginine acetate (L-NMMA, 300 μM). [3H]-NA release induced by NIC (100 μM) was attenuated by methylene blue (3 μM) and 1H-[1,2,4]oxadiazole[4,3-α]quinoxalin-1-one (ODQ, 10 μM), and enhanced by zaprinast (30 μM).In conclusion, NIC stimulates the release of [3H]-NA through activation of α-BTX-insensitive nicotinic acetylcholine receptors in the human cerebral cortex slices and this action of NIC is associated with modulation of the NO/cGMP pathway.
Nicotine; noradrenaline release; human cerebral cortex