a(MESH:Neurons)
For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515). PubMed:19126755
Acetylcholine (ACh) is a neurotransmitter that modulates neuronal function in several areas of the CNS associated with AD and/or SZ pathology, including the striatum, cortex, hippocampus, and prefrontal cortex.5 ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs). PubMed:24511233
Given its widespread distribution in the brain, it is not surprising that cholinergic neurotransmission is responsible for modulating important neural functions PubMed:26813123
Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation PubMed:21482353
These findings indicate that suppression of the cholinergic system by lynx proteins stabilizes neural circuitry PubMed:21482353
Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127. PubMed:19721446
nAChRs are particularly important in two critical periods of brain life: early pre- and post-natal circuit formation, and age-related cell degeneration. They are involved in neuronal survival, as it has been shown that nicotinic agonists are neu- roprotective in in vivo and in vitro models PubMed:28901280
nAChRs are particularly important in two critical periods of brain life: early pre- and post-natal circuit formation, and age-related cell degeneration. They are involved in neuronal survival, as it has been shown that nicotinic agonists are neu- roprotective in in vivo and in vitro models PubMed:28901280
Adenosine downmodulates neuronal activity (cFos levels), impairs the presynapse, and attenuates long-term potentiation (LTP) via the A1 receptor (21) PubMed:27671637
64627 increases neuronal activity (Fos mRNA) both in proaggregant Tau transgenic slices and controls, although in case of the proaggregant slices neuronal activity is almost doubled, yielding levels similar to those of treated littermate control slices (Fig. 4D) PubMed:27671637
Having observed that 64627 restores presynaptic functioning (i.e., PPF, Fig. 4F), neuronal activity (induction of Fos, Fig. 4D), and dendritic spine levels in proaggregant Tau transgenic organotypic slices (Fig. 5 A and B), we tested whether we could restore long-term spatial memory in proaggregant Tau transgenic mice as well PubMed:27671637
Surprisingly, expression of neuronal activity marker cFos, astrocytic activity marker Gfap, and oxidative stress marker Hmox1 were reduced in the proaggregant Tau transgenic slices, whereas antiaggregant Tau transgenic slices were not different from littermate controls (Fig. 4A) PubMed:27671637
Adenosine downmodulates neuronal activity (cFos levels), impairs the presynapse, and attenuates long-term potentiation (LTP) via the A1 receptor (21) PubMed:27671637
Surprisingly, expression of neuronal activity marker cFos, astrocytic activity marker Gfap, and oxidative stress marker Hmox1 were reduced in the proaggregant Tau transgenic slices, whereas antiaggregant Tau transgenic slices were not different from littermate controls (Fig. 4A) PubMed:27671637
This revealed an impressive increase in mature neurons in all regions of the hippocampus (47% in CA1; 69% in CA3 and 81% in DG) in the anti-aggregant TauRDΔKPP slices compared to age-matched controls (Fig. 2c, bars 2, 5 and 8) PubMed:29202785
Notably, after switch-off of antiaggregant TauRDΔKPP there was a change in the number of BrdU stained cells in all regions of the hippocampus (CA1 region 32%, CA3 region 22% and DG 33% reduction) compared to switch-ON conditions (Fig. 7a, bars 4, 8 and 12) PubMed:29202785
Similarly in the number of NeuN positive cells, there was a 22% reduction in CA1, 33% in CA3 and 37% reduction in DG compared to switch-On conditions (Fig. 7b, bars 4, 8 and 12) PubMed:29202785
BrdU positive cells were present in CA1, CA3 and DG in both the controls and antiaggregant TauRDΔKPP groups (Fig. 8a, b), but their numbers were increased strongly by 80% only in the CA3 region of the anti-aggregant TauRDΔKPP mice (Fig. 8b, bar 4), with 20% change in the CA1 and no change in the DG (Fig. 8b, bar 2 and 6) PubMed:29202785
Additionally, there was an increase by 25% of the hippocampal volume in anti-aggregant TauRDΔKPP mice, compared to controls at P8 (Fig. 8c, bar 2), presumably due to the increased number of neurons PubMed:29202785
Surprisingly, the anti-aggregant TauRDΔKPP mice had an increased neuronal number significantly in the CA3 region (20%, Fig. 9b, bar 5), in contrast to the pro-aggregant TauRDΔK mice where neuronal loss (e.g. CA1 ~50%, CA3 ~10%, DG ~25%) was observed in all regions of the hippocampus (Fig. 9b, bar 3, 6, 9) PubMed:29202785
This suggests that the expression of anti-aggregant TauRDΔKPP is needed for the increased proliferation of newborn neurons, and since these new born neurons need endogenous mouse Tau for their migration, differentiation, and maturation, there is enhanced expression of endogenous mouse Tau PubMed:29202785
This may be due to the strong Tau pathology of the toxic pro-aggregant TauRDΔK leading to Tau aggregation, loss of synapses and loss of neurons PubMed:29202785
By contrast, the pro-aggregant TauRDΔK slices showed a pronounced reduction in neuronal numbers, particularly in the CA1 (-44%), CA3 (-33%) and DG (-22%) regions compared to controls (Fig. 2c, bars 3, 6 and 9) PubMed:29202785
Surprisingly, the anti-aggregant TauRDΔKPP mice had an increased neuronal number significantly in the CA3 region (20%, Fig. 9b, bar 5), in contrast to the pro-aggregant TauRDΔK mice where neuronal loss (e.g. CA1 ~50%, CA3 ~10%, DG ~25%) was observed in all regions of the hippocampus (Fig. 9b, bar 3, 6, 9) PubMed:29202785
the application of extracellular tau increases the electrical activity of iPSC-derived or primary cortical neurons PubMed:29238289
Moreover, extracellular tau may elicit cellular toxicity under certain conditions. PubMed:29238289
this observation suggests that the activity-dependent release of tau participates in a positive feedback loop on neuronal activity. PubMed:29238289
The addition of tau into the cell culture media binds to muscarinic acetylcholine receptors and increases intracellular calcium, eventually leading to cell death PubMed:29238289
We found that in the visual cortex, neurons containing conspicuous quantities of mislocalized and aggregated tau nonetheless appear to have a normal capacity to integrate dendritic inputs and respond robustly to visual stimuli and also maintain normal somatic baseline calcium levels. In particular, we show that individual NFT-bearing neurons can respond robustly after integrating sensory inputs and are functionally indistinguishable from neighboring non–NFT-bearing neurons. These results demonstrate that NFT-bearing neurons remain functionally integrated in cortical circuits. PubMed:24368848
We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain. EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein. PubMed:23531502
We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first PubMed:29276758
Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PubMed:27087442
Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PubMed:27087442
Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PubMed:27087442
Accumulation of misfolded proteins and damaged organelles is highly detrimental for neuronal homeostasis and survival. PubMed:29758300
Although key to the survival of all cells, endocytosis supports unique neuronal functions, including aspects of synaptic transmission and plasticity underlying memory and learning. PubMed:22908190
As shown earlier, TauRDΔK-expressing mice display loss of neurons in the CA3 and other regions of the hippocampus [11,24]. PubMed:28528849
Indeed, evidence from both human and mouse studies indicates that soluble oligomers rather than insoluble aggregates are toxic to normal neurons (70). PubMed:29191965
Similarly, elimination of CDK-5 improved the touch response in the mutant TauR406W-line, but failed to improve it inother line PubMed:29191965
Frontotemporal dementia with parkinsonism–mutant tau expression (0N4R-tau P301L and 0N4R-tau R406W), on the other hand, resulted in a reduced touch response that worsened with age PubMed:29191965
At the later stages, the mutant-tau lines showed microtubule loss and non-apoptotic neuronal death, paralleled by a complete loss of touch response (62). PubMed:29191965
Frontotemporal dementia with parkinsonism–mutant tau expression (0N4R-tau P301L and 0N4R-tau R406W), on the other hand, resulted in a reduced touch response that worsened with age PubMed:29191965
At the later stages, the mutant-tau lines showed microtubule loss and non-apoptotic neuronal death, paralleled by a complete loss of touch response (62). PubMed:29191965
Although the wild-type tau lines showed a mild late-onset dose-dependent Unc phenotype, TauA152T worms showed early-onset paralysis and acute neuronal dysfunction. PubMed:29191965
In the longer term, however, these tau aggregates may sequester other cell components, finally compromising neuronal functions PubMed:26631930
These studies indicate that the endogenous tau plays a part in regulating neuronal activity PubMed:26631930
Intraneuronal iron accumulation, neuronal loss in the substantia nigra and a severe decline in locomotor functions were observed in 12‑month-old tau-knockoutmice PubMed:26631930
Although tau function can be partly compensated by other, redundant microtubule-associated proteins (for example, MAP1A), the behavioural impairments observed in aged (~12‑month-old) tau-knockout mice indicate that tau is necessary for normal neuronal and brain function. PubMed:26631930
Metabolic degradation of nicotine and rapid clearance is a mechanism that protects neurons from greater nicotine concentrations, since nicotine readily crosses the mammalian blood-brain barrier and accumulates in the lipophilic brain environment to concentrations that may exceed plasma concentrations by one order of magnitude. Nevertheless, neurotoxicity to nicotine is not uncommon, as attested to by the recent increase in hospital emergency room visits by smokers who concurrently use the transdermal nicotine patch (503). PubMed:19126755
For instance, the alpha3 nAChR transcript generally dominates in the prenatal brain or in injured neurons, whereas its expression tends to be downregulated in the adult or healthy neuron, and alpha4 transcription is increased. PubMed:19126755
For instance, the alpha3 nAChR transcript generally dominates in the prenatal brain or in injured neurons, whereas its expression tends to be downregulated in the adult or healthy neuron, and alpha4 transcription is increased. PubMed:19126755
For example, while the alpha7 nAChR is primarily a homomeric receptor in neurons (127), combinations of alpha7 nAChR subunits with alpha5, beta2, or beta3 nAChR subunits have been reported to form functional heteromeric receptors in some systems (240, 360, 515). PubMed:19126755
Interestingly, astrocytic KYNA production is regulated by neuronal activity (187) and cellular energy metabolism (213). This dependence of extracellular KYNA concentrations on the functional interplay between neurons and astrocytes is in line with the postulated neuromodulatory role of KYNA (418) and adds to the complexity of the neurochemical networks in the brain. PubMed:19126755
Because excess activation of nAChRs damages neuronal health and brain function, organisms have a clear need to restrict the degree of nAChR activation PubMed:21482353
The neurons release additional GABA, activating presynaptic GABAB receptors on the excitatory inputs to pyramidal neurons, which diminish the release of glutamate onto the pyramidal neurons (Figure 2) PubMed:21482353
nAChRs are particularly important in two critical periods of brain life: early pre- and post-natal circuit formation, and age-related cell degeneration. They are involved in neuronal survival, as it has been shown that nicotinic agonists are neu- roprotective in in vivo and in vitro models PubMed:28901280
Surprisingly, expression of neuronal activity marker cFos, astrocytic activity marker Gfap, and oxidative stress marker Hmox1 were reduced in the proaggregant Tau transgenic slices, whereas antiaggregant Tau transgenic slices were not different from littermate controls (Fig. 4A) PubMed:27671637
In addition, stimulating neuronal activity in either cultured neurons or in vivo also enhances tau release PubMed:29238289
this observation suggests that the activity-dependent release of tau participates in a positive feedback loop on neuronal activity. PubMed:29238289
CSF tau in APP transgenic mice is increased in an age- dependent manner without a global neuronal loss PubMed:29238289
These observations suggest that CaMKv blocks RhoA activity by preventing its interaction with Lfc. These results demonstrate that CaMKv regulates spine maintenance through RhoA inhibition. The suppression of the Lfc/RhoA pathway by AMPA receptors is implicated in dendritic spine maintenance10. Given that CaMKv expression is upregulated by synaptic activity, CaMKv may be a key signalling protein that transduces the signals from AMPA receptors to suppress RhoA during activity-dependent spine maintenance. Corroborating this, the AMPA receptor blocker NBQX attenuated CaMKv expression in neurons (Fig. 3i,j). Importantly, CaMKv overexpression completely rescued NBQX-induced spine loss (Fig. 3k,l). These findings collectively reveal that activity-dependent CaMKv expression and the subsequent inhibition of Lfc/RhoA are required to mediate AMPA receptor function in spine maintenance. PubMed:27796283
Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PubMed:27087442
Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PubMed:27087442
Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi. PubMed:27087442
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