scholarly journals Amyloid beta oligomers modulate neuronal autophagy through the primary cilium

2021 ◽  
Author(s):  
Olatz Pampliega ◽  
Federico N. Soria ◽  
Narayana Pineda-Ramirez ◽  
Erwan Bezard
Keyword(s):  
Neurodegenerative Diseases ◽  
Amyloid Beta ◽  
Primary Cilium ◽  
Adult Brain ◽  
Dependent Manner ◽  
Aβ Oligomers ◽  
App Processing ◽  
Age Dependent ◽  
Aβ Generation

The major neurodegenerative diseases, like Alzheimer disease (AD), accumulate neuropathogenic proteins that compromise autophagic function. In AD, autophagy contributes to intracellular APP processing and amyloid beta (Aβ) generation by mutant presenilin-1 (PS1). However, how extracellular soluble Aβ oligomers (Aβo) impact intracellular autophagy is not well understood. The primary cilium (PC), a signaling organelle on the surface of mature neurons and glia, is able to bind Aβ. Since PC signaling pathways knowingly modify autophagy in non-brain cells, we here investigated the role of neuronal PC in the modulation of autophagy during acute extracellular Aβo overload. Our results show that, in vivo, recombinant Aβo require the presence of neuronal PC to modulate early autophagy and to induce the accumulation of autophagic vacuoles in an age-dependent manner. We show that activated Akt mediates these effects in an age-dependent manner, and that ciliary p75NTR receptor is required to block autophagy by Aβo. These findings demonstrate that neuronal PC in the adult brain participates in the deleterious effects mediated by soluble Aβo. The PC should therefore be considered as a target organelle to modulate autophagy for the treatment of neurodegenerative diseases.

scholarly journals Chiral Effect at Nano-Bio Interface: A Model of Chiral Gold Nanoparticle on Amylin Fibrillation

Nanomaterials ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 412 ◽  
Author(s):  
Jing Li ◽  
Rui Chen ◽  
Shasha Zhang ◽  
Zhongjie Ma ◽  
Zhuoying Luo ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Chemical Properties ◽  
Transition Process ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Interesting Insight ◽  
Α Helix ◽  
Physical And Chemical ◽  
Conformation Transition

Protein/Peptide amyloidosis is the main cause of several diseases, such as neurodegenerative diseases. It has been widely acknowledged that the unnatural fibrillation of protein/peptides in vivo is significantly affected by the physical and chemical properties of multiscale biological membranes. For example, previous studies have proved that molecule chirality could greatly influence the misfolding, fibrillation and assembly of β-Amyloid peptides at the flat liquid-solid surface. However, how the nanoscale chirality influences this process remains unclear. Here we used gold nanoparticles (AuNPs, d = 4 ± 1 nm)—modified with N-isobutyl-L(D)-cysteine (L(D)-NIBC) enantiomers—as a model to illustrate the chiral effect on the amylin fibrillation at nano-bio interface. We reported that both two chiral AuNPs could inhibit amylin fibrillation in a dosage-dependent manner but the inhibitory effect of L-NIBC-AuNPs was more effective than that of D-NIBC-AuNPs. In-situ real time circular dichroism (CD) spectra showed that L-NIBC-AuNPs could inhibit the conformation transition process of amylin from random coils to α-helix, while D-NIBC-AuNPs could only delay but not prevent the formation of α-helix; however, they could inhibit the further conformation transition process of amylin from α-helix to β-sheet. These results not only provide interesting insight for reconsidering the mechanism of peptides amyloidosis at the chiral interfaces provided by biological nanostructures in vivo but also would help us design therapeutic inhibitors for anti-amyloidosis targeting diverse neurodegenerative diseases.

scholarly journals Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1113
Author(s):  
Pamela Maher
Keyword(s):  
Transition Metals ◽  
Neurodegenerative Diseases ◽  
Dependent Manner ◽  
Copper Binding ◽  
Drug Candidates ◽  
Beneficial Effects ◽  
Anti Inflammatory ◽  
Dose Dependent

Alterations occur in the homeostasis of the transition metals iron (Fe2+) and copper (Cu2+) during aging and these are further amplified in neurodegenerative diseases, including Alzheimer’s disease (AD). These observations suggest that the most effective drug candidates for AD might be those that can reduce these alterations. The flavonoid fisetin has both neuroprotective and anti-inflammatory activity both in vitro and in vivo and can bind both iron and copper suggesting that its chelating activity might play a role in its beneficial effects. To test this idea, the effects of iron and copper on both the neuroprotective and anti-inflammatory activities of fisetin were examined. It is shown that while fisetin can reduce the potentiation of cell death by iron and copper in response to treatments that lower glutathione levels, it is much less effective when the metals are combined with other inducers of oxidative stress. In addition, iron but not copper reduces the anti-inflammatory effects of fisetin in a dose-dependent manner. These effects correlate with the ability of iron but not copper to block the induction of the antioxidant transcription factor, Nrf2, by fisetin. In contrast, although the flavanone sterubin also binds iron, the metal has no effect on sterubin’s ability to induce Nrf2 or protect cells from toxic or pro-inflammatory insults. Together, these results suggest that while iron and copper binding could contribute to the beneficial effects of neuroprotective compounds in the context of neurodegenerative diseases, the consequences of this binding need to be fully examined for each compound.

Mechanotransductive Effects of Acoustic Radiation Force on Osteoblastic Primary Cilium, Cytoskeleton and Ca2+ Influx

2012 ◽  
Author(s):  
Y. X. Qin ◽  
S. Zhang ◽  
J. Cheng
Keyword(s):  
Primary Cilium ◽  
Bone Cells ◽  
Acoustic Radiation ◽  
Biological Effects ◽  
Radiation Force ◽  
Acoustic Radiation Force ◽  
Dependent Manner ◽  
Wide Range

Mechanotransduction has demonstrated potentials for tissue adaptation in vivo and in vitro. It is well documented that ultrasound, as a mechanical signal, can produce a wide variety of biological effects in vitro and in vivo[1]. For example, pulsed ultrasound can be used to accelerate the rate of bone fracture healing noninvasively. Although a wide range of studies have been done, mechanism for this therapeutic effect on bone healing is currently unknown and still under active investigation. In our previous studies, we have developed methodology allowed in vitro manipulating osteoblastic cells using acoustic radiation force (ARF) generated by ultrasound without the effects of acoustic streaming and ultrasound-induced temperature rise. Furthermore, we also confirmed that ARF modulated intracellular Ca2+ transient in MC3T3-E1 osteoblast-like cells in a strain and frequency-dependent manner. A potential mechanism by which bone cells may sense ultrasound is through their structures such as primary cilia and cytoskeletons. The purpose of the current study was to evaluate the hypothesis that acoustic radiation force can regulate the activities of the primary cilium and the cytoskeleton of the cells, which act as the mechanotransductive signals to mediate Ca2+ flux, as a pathway in response to cyclic loading.

scholarly journals Robust RBM3 and β-klotho expression in developing neurons in the human brain

2019 ◽  
Vol 39 (12) ◽  
pp. 2355-2367 ◽  
Author(s):  
Travis C Jackson ◽  
Keri Janesko-Feldman ◽  
Shaun W Carlson ◽  
Shawn E Kotermanski ◽  
Patrick M Kochanek
Keyword(s):  
Cortical Neurons ◽  
Rna Binding ◽  
Transmembrane Protein ◽  
Adult Brain ◽  
Human Infant ◽  
Fibroblast Growth Factor 21 ◽  
Binding Motif ◽  
Dependent Manner ◽  
Neuroprotective Effects

RNA binding motif 3 (RBM3) is a powerful neuroprotectant that inhibits neurodegenerative cell death in vivo and is a promising therapeutic target in brain ischemia. RBM3 is increased by the hormone fibroblast growth factor 21 (FGF21) in an age- and temperature-dependent manner in rat cortical neurons. FGF21 receptor binding is controlled by the transmembrane protein β-klotho, which is mostly absent in the adult brain. We discovered that RBM3/β-klotho is unexpectedly high in the human infant vs. adult brain (hippocampus/prefrontal cortex). The use of tissue homogenates in that study precluded a comparison of RBM3/β-klotho expression among different CNS cell-types, thus, omitted key evidence (i.e. confirmation of neuronal expression) that would otherwise provide a critical link to support their possible direct neuroprotective effects in humans. This report addresses that knowledge gap. High-quality fixed human hippocampus, cortex, and hypothalamic tissues were acquired from the NIH Neurobiobank (<1 yr (premature born) infants, 1 yr, 4 yr, and 34 yr). Dual labeling of cell-type markers vs. RBM3/β-klotho revealed enriched staining of targets in neurons in the developing brain. Identifying that RBM3/β-klotho is abundant in neurons in the immature brain is fundamentally important to guide protocol design and conceptual frameworks germane to future testing of these neuroprotective pathways in humans.

scholarly journals Functional involvement of carbonic anhydrase in calcium transport of the chick chorioallantoic membrane

1978 ◽  
Vol 176 (1) ◽  
pp. 67-74 ◽  
Author(s):  
R S Tuan ◽  
J Zrike
Keyword(s):  
Carbonic Anhydrase ◽  
Chorioallantoic Membrane ◽  
Carbonic Anhydrase Activity ◽  
Calcium Deposition ◽  
Dependent Manner ◽  
Transport Activity ◽  
In Ovo ◽  
Chick Chorioallantoic Membrane ◽  
Age Dependent

Carbonic anhydrase activity was demonstrated in the chick-embryonic chorioallantoic membrane and was correlated with the Ca2+-transport activity of the membrane. It is inhibited by sulphonamides and is expressed in the chorioallantoic membrane in an age-dependent fashion during embryonic development. Ca2+ uptake by the chorioallantoic membrane in vivo also increases in a similar age-dependent manner. The temporal increase in these activities is coincident with calcium deposition in the embryonic skeleton. Incubation of the chorioallantoic membrane in ovo with sulphonamides specifically inhibits both the carbonic anhydrase and the Ca2+ uptake activities of the membrane in vivo. Enzyme histochemistry revealed the carbonic anhydrase activity is localized in the Ca2+-transporting ectodermal cells of the chorioallantoic membrane. These results, taken together, indicate that carbonic anhydrase may be functionally important in the Ca2+-transport activity of the chorioallantoic membrane.

Na(+)-K(+)-ATPase gene expression during in vitro development of rat fetal forebrain

1990 ◽  
Vol 258 (6) ◽  
pp. C1062-C1069 ◽  
Author(s):  
I. Corthesy-Theulaz ◽  
A. M. Merillat ◽  
P. Honegger ◽  
B. C. Rossier
Keyword(s):  
Cell Cultures ◽  
Specific Activity ◽  
Relative Rate ◽  
Adult Brain ◽  
Similar Proportion ◽  
Neuronal Cultures ◽  
Dependent Manner ◽  
Atpase Gene

The existence of at least three isoforms of Na(+)-K(+)-ATPase in adult brain tissues [alpha 1, kidney type; alpha 2 [or alpha(+)]; alpha 3] suggests that these genes might be regulated in a cell-specific and time-dependent manner during development. We have studied this question in serum-free aggregating cell cultures of mechanically dissociated rat fetal telencephalon. At the protein level, the relative rate of synthesis of the pool of alpha 1-, alpha 2-, and alpha 3-subunits increased approximately twofold over 15 days of culture, leading to a marked increase in the immunochemical pool of alpha-subunits as measured by a panspecific polyclonal antibody. Concomitantly, Na(+)-K(+)-ATPase enzyme-specific activity increased three- (lower forebrain) to sixfold (upper forebrain). The transcripts of all three alpha-isoforms and beta-subunit were detected in vitro in similar proportion to the level observed in vivo. alpha 3-mRNA (3.7 kb) was more abundant than alpha 1 (3.7 kb) or alpha 2 (5.3 and 3.4 kb). Cytosine arabinoside (0.4 microM) and cholera toxin (0.1 microM) were used to selectively eliminate glial cells or neurons, respectively. It was found that alpha 2-mRNA is predominantly transcribed in glial cell cultures, whereas alpha 3- and beta 1-mRNA (2.7, 2.3, and 1.8 kb) are predominant in neuronal cultures.

scholarly journals Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death

2021 ◽  
Vol 22 (16) ◽  
pp. 8394
Author(s):  
Yang Zhao ◽  
Fulei Tang ◽  
Daehoon Lee ◽  
Wen-Cheng Xiong
Keyword(s):  
Fusion Protein ◽  
Neurodegenerative Diseases ◽  
Neonatal Death ◽  
Terminal Differentiation ◽  
Dependent Manner ◽  
Transgenic Mouse Line ◽  
Low Level ◽  
Neurodegenerative Pathology ◽  
Age Dependent ◽  
Vacuolar Protein

Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death. The relationships among these phenotypes and the underlying mechanisms remain largely unclear. Here, we provide evidence that expression of low level of VPS35-mCherry fusion protein in Vps35Neurod6 mice could diminish the phenotypes in an age-dependent manner. Specifically, we have generated a conditional transgenic mouse line, LSL-Vps35-mCherry, which expresses VPS35-mCherry fusion protein in a Cre-dependent manner. Crossing LSL-Vps35-mCherry with Vps35Neurod6 to obtain TgVPS35-mCherry, Vps35Neurod6 mice prevent the neonatal death and diminish the dendritic morphogenesis deficit and gliosis at the neonatal, but not the adult age. Further studies revealed that the Vps35-mCherry transgene expression was low, and the level of Vps35 mRNA comprised only ~5–7% of the Vps35 mRNA of control mice. Such low level of VPS35-mCherry could restore the amount of other retromer components (Vps26a and Vps29) at the neonatal age (P14). Importantly, the neurodegenerative pathology presented in the survived adult TgVps35-mCherry; Vps35Neurod6 mice. These results demonstrate the sufficiency of low level of VPS35-mCherry fusion protein to diminish the phenotypes in Vps35Neurod6 mice at the neonatal age, verifying a key role of neuronal Vps35 in stabilizing retromer complex proteins, and supporting the view for Vps35 as a potential therapeutic target for neurodegenerative diseases.

scholarly journals Disruption of the MAP1B-related Protein FUTSCH Leads to Changes in the Neuronal Cytoskeleton, Axonal Transport Defects, and Progressive Neurodegeneration in Drosophila

2005 ◽  
Vol 16 (5) ◽  
pp. 2433-2442 ◽  
Author(s):  
Alexandre Bettencourt da Cruz ◽  
Martin Schwärzel ◽  
Sabine Schulze ◽  
Mahtab Niyyati ◽  
Martin Heisenberg ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Axonal Transport ◽  
Fragile X ◽  
Adult Brain ◽  
In Vivo Model ◽  
Microtubule Network ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
Progressive Neurodegeneration

The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futscholk primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futscholk. A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futscholk mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system.

scholarly journals The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin

2019 ◽  
Author(s):  
Qin Cao ◽  
Daniel H. Anderson ◽  
Wilson Liang ◽  
Joshua Chou ◽  
Lorena Saelices
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Amyloid Plaques ◽  
Inhibitory Effect ◽  
Aβ Oligomers ◽  
Transthyretin Amyloidosis ◽  
Cellular Toxicity ◽  
Aβ Aggregation

AbstractThe protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (Aβ), associated with Alzheimer’s disease, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits Aβ oligomer formation and also promotes the formation of non-toxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer’s patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer’s disease.Significance statementThe pathological landmarks of Alzheimer’s disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (Aβ). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects Aβ from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by Aβ. In addition, we identified a minimum segment of TTR that inhibits Aβ aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.

scholarly journals A neural m6A/YTHDF pathway is required for learning and memory in Drosophila

2020 ◽  
Author(s):  
Lijuan Kan ◽  
Stanislav Ott ◽  
Brian Joseph ◽  
Eun Sil Park ◽  
Crystal Dai ◽  
...  
Keyword(s):  
Short Term Memory ◽  
Rna Stability ◽  
Model Organism ◽  
Translational Efficiency ◽  
Neural Function ◽  
Dependent Manner ◽  
Genomic Analyses ◽  
Age Dependent ◽  
Functional Analyses

AbstractThe roles of epitranscriptomic modifications in mRNA regulation have recently received substantial attention, with appreciation growing for their phenotypically selective impacts within the animal. We adopted Drosophila melanogaster as a model system to study m6A, the most abundant internal modification of mRNA. Here, we report proteomic and functional analyses of fly m6A-binding proteins, confirming nuclear (YTHDC) and cytoplasmic (YTHDF) YTH domain proteins as the major m6A binders. Since all core m6A pathway mutants are viable, we assessed in vivo requirements of the m6A pathway in cognitive processes. Assays of short term memory revealed an age-dependent requirement of m6A writers working via YTHDF, but not YTHDC, comprising the first phenotypes assigned to Drosophila mutants of the cytoplasmic m6A reader. These factors promote memory via neural-autonomous activities, and are required in the mushroom body, the center for associative learning. To inform their basis, we mapped m6A from wild-type and mettl3 null mutant heads, allowing robust discrimination of Mettl3-dependent m6A sites. In contrast to mammalian m6A, which is predominant in 3’ UTRs, Drosophila m6A is highly enriched in 5’ UTRs and occurs in an adenosine-rich context. Genomic analyses demonstrate that Drosophila m6A does not directionally affect RNA stability, but is preferentially deposited on genes with low translational efficiency. However, functional tests indicate a role for m6A in translational activation, since we observe reduced nascent protein synthesis in mettl3-KO cells. Finally, we show that ectopic YTHDF can increase m6A target reporter output in an m6A-binding dependent manner, and that this activity is required for in vivo neural function of YTHDF in memory. Altogether, we provide the first tissue-specific m6A maps in this model organism and reveal selective behavioral and translational defects for m6A/YTHDF mutants.

Sign in / Sign up

Export Citation Format

Share Document