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Article ; Online: Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.

Almeida, Michael F / Farizatto, Karen L G / Almeida, Renato S / Bahr, Ben A

2023 Volume 93, Page(s) 102162

Abstract: Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related ... ...

Abstract	Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related dementias such as Alzheimer's disease, and the aging process is known to be influenced by life events that can positively or negatively affect age-related diseases. Remarkably, life experiences that make the brain vulnerable to dementia, such as seizure episodes, neurotoxin exposures, metabolic disorders, and trauma-inducing events (e.g. traumatic injuries or mild neurotrauma from a fall or blast exposure), have been associated with negative effects on proteostasis and synaptic integrity. Functional compromise of the autophagy-lysosomal pathway, a major contributor to proteostasis, has been implicated in Alzheimer's disease, Parkinson's disease, obesity-related pathology, Huntington's disease, as well as in synaptic degeneration which is the best correlate of cognitive decline. Correspondingly, pharmacological and non-pharmacological strategies that positively modulate lysosomal proteases are recognized as synaptoprotective through degradative clearance of pathogenic proteins. Here, we discuss life-associated vulnerabilities that influence key hallmarks of brain aging and the increased burden of age-related dementias. Additionally, we discuss exercise and diet among the lifestyle strategies that regulate proteostasis as well as synaptic integrity, leading to evident prevention of cognitive deficits during brain aging in pre-clinical models.
MeSH term(s)	Humans ; Alzheimer Disease/prevention & control ; Alzheimer Disease/complications ; Proteostasis ; Cognitive Dysfunction/prevention & control ; Cognitive Dysfunction/metabolism ; Life Style ; Proteostasis Deficiencies
Language	English
Publishing date	2023-12-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2075672-0
ISSN	1872-9649 ; 1568-1637
ISSN (online)	1872-9649
ISSN	1568-1637
DOI	10.1016/j.arr.2023.102162
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Article ; Online: A single pathway targets several health challenges of the elderly.

Bahr, Ben A

Rejuvenation research

2014 Volume 17, Issue 4, Page(s) 382–384

Abstract: New avenues to modulate the autophagy-lysosomal route of protein clearance have the potential to help treat several disease states to which the elderly are particularly vulnerable. Two recent papers identified distinct ways to tap into the lysosomal ... ...

Abstract	New avenues to modulate the autophagy-lysosomal route of protein clearance have the potential to help treat several disease states to which the elderly are particularly vulnerable. Two recent papers identified distinct ways to tap into the lysosomal degradation pathway of autophagy to reduce age-related protein accumulation events. Shoji-Kawata et al. (Nature 2013;494:201-206) describe a new autophagy-inducing peptide, Tat-Beclin 1, that enhances the clearance of polyglutamine aggregates related to Huntington's disease and, interestingly, suppresses viral and bacterial infections. Savolainen et al. (Neurobiol Dis 2014;68:1-15) describe a prolyl oligopeptidase inhibitor that reduces α-synuclein species related to Parkinson's disease and other α-synucleinopathies, and this inhibitor caused a concomitant increase in autophagic activation markers. Previous studies have also linked the autophagy-lysosomal pathway to the protective clearing of the Aβ peptides of Alzheimer's disease and tau species of tauopathies. Enhancing autophagy-lysosomal efficiency may provide a therapeutic avenue for diverse types of proteinopathies, including the most common neurodegenerative disorders of the elderly.
MeSH term(s)	Animals ; Apoptosis Regulatory Proteins/chemistry ; Apoptosis Regulatory Proteins/therapeutic use ; Autophagy/drug effects ; Brain Diseases/genetics ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/therapeutic use ; Peptide Fragments/chemistry ; Peptide Fragments/pharmacology ; Proline/analogs & derivatives ; Serine Endopeptidases/metabolism ; Serine Proteinase Inhibitors/therapeutic use ; alpha-Synuclein/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; Membrane Proteins ; Peptide Fragments ; Serine Proteinase Inhibitors ; alpha-Synuclein ; Proline (9DLQ4CIU6V) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2014-08
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	2150779-X
ISSN	1557-8577 ; 1549-1684
ISSN (online)	1557-8577
ISSN	1549-1684
DOI	10.1089/rej.2014.1585
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Article ; Online: Endosomal-lysosomal dysfunction in metabolic diseases and Alzheimer's disease.

Almeida, Michael F / Bahr, Ben A / Kinsey, Stephen T

International review of neurobiology

2020 Volume 154, Page(s) 303–324

Abstract: The endosomal-lysosomal pathways and related autophagic processes are responsible for proteostasis, involving complexes between lysosomes and autophagosomes. Lysosomes are a key component of homeostasis, involved in cell signaling, metabolism, and ... ...

Abstract	The endosomal-lysosomal pathways and related autophagic processes are responsible for proteostasis, involving complexes between lysosomes and autophagosomes. Lysosomes are a key component of homeostasis, involved in cell signaling, metabolism, and quality control, and they experience functional compromise in metabolic diseases, aging, and neurodegenerative diseases. Many genetic mutations and risk factor genes associated with proteinopathies, as well as with metabolic diseases like diabetes, negatively influence endocytic trafficking and autophagic clearance. In contrast, health-improving exercise induces autophagy-lysosomal degradation, perhaps promoting efficient digestion of injured organelles so that undamaged organelles ensure cellular healthiness. Reductions in lysosomal hydrolases are implicated in Alzheimer's, Parkinson's, and lysosomal storage diseases, as well as obesity-related pathology, and members of the cathepsin enzyme family are involved in clearing both Aβ42 and α-synuclein. Upregulation of cathepsin hydrolases improves synaptic and memory functions in models of dementia and in exercising humans, thus identifying lysosomal-related systems as vital for healthy cognitive aging.
MeSH term(s)	Aging/metabolism ; Alzheimer Disease/metabolism ; Animals ; Diabetes Mellitus/metabolism ; Exercise/physiology ; Humans ; Lysosomes/metabolism ; Metabolic Diseases/metabolism ; Metabolic Networks and Pathways/physiology ; Obesity/metabolism ; Proteostasis/physiology ; Synucleinopathies/metabolism
Language	English
Publishing date	2020-07-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	209876-3
ISSN	2162-5514 ; 0074-7742
ISSN (online)	2162-5514
ISSN	0074-7742
DOI	10.1016/bs.irn.2020.02.012
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Article: Paraoxon: An Anticholinesterase That Triggers an Excitotoxic Cascade of Oxidative Stress, Adhesion Responses, and Synaptic Compromise.

Farizatto, Karen L G / Bahr, Ben A

European scientific journal

2018 Volume 13, Page(s) 29–37

Abstract: The anticholinesterase paraoxon (Pxn) is an organophosphate (OP) and the active metabolite of the insecticide parathion. It potently inhibits the enzyme acetylcholinesterase and leads to enhanced glutamate release, diminished GABA uptake, oxidative ... ...

Abstract	The anticholinesterase paraoxon (Pxn) is an organophosphate (OP) and the active metabolite of the insecticide parathion. It potently inhibits the enzyme acetylcholinesterase and leads to enhanced glutamate release, diminished GABA uptake, oxidative damage, and neurodegeneration. The resulting increased levels of acetylcholine can trigger seizures and cause neuronal and excitotoxic damage in the brain. The brain susceptibility related to anticholinesterase toxins extends beyond potential brain damage and death from toxic levels of the agent. Asymptomatic low-level exposure to such toxins can also leave the brain vulnerable or even cause it to exhibit neurological problems later in life. The actions of Pxn and similar neurotoxins have been studied in order to examine the events associated with anticholinesterase toxicity in the brain. A recent study demonstrated that Pxn exposure initiates a pathogenic cascade involving seizure events and subsequent signs of damage including unique presynaptic vulnerability and associated behavioral deficits. In addition, Pxn-mediated synaptotoxicity is also associated with enhanced production of oxidative stress as well as integrin adhesion responses. These findings provide a better understanding of the molecular events involved in Pxn toxicity.
Language	English
Publishing date	2018-05-21
Publishing country	France
Document type	Journal Article
ZDB-ID	2648284-8
ISSN	1857-7431 ; 1857-7881
ISSN (online)	1857-7431
ISSN	1857-7881
DOI	10.19044/esj.2017.c1p4
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Article ; Online: Lysosomal modulatory drugs for a broad strategy against protein accumulation disorders.

Bahr, Ben A

Current Alzheimer research

2009 Volume 6, Issue 5, Page(s) 438–445

Abstract: Protein accumulation leads to CNS effects in Alzheimer's disease, frontotemporal dementia, and other age-related disorders. Common mechanisms may contribute to the progressive pathology in the different protein accumulation disorders, and synergistic ... ...

Abstract	Protein accumulation leads to CNS effects in Alzheimer's disease, frontotemporal dementia, and other age-related disorders. Common mechanisms may contribute to the progressive pathology in the different protein accumulation disorders, and synergistic toxicity between dissimilar protein structures may also be involved. Among several avenues being pursued to reduce proteins prone to oligomerization and/or aggregation, a lysosomal avenue has been described that regulates the lysosomal system's broad clearance capability. Lysosomes are the primary site for protein clearance, to remove old and misfolded proteins and maintain cellular homeostasis. Small-molecule lysosomal modulators trigger a feedback response in vitro and in vivo, resulting in marked up-regulation of cathepsins and other lysosomal enzymes without any indications of synaptic pathology, behavioral abnormalities, or major organ malfunctions. For the characterization and screening of lysosomal modulatory drugs, the hippocampal slice model of protein accumulation has proved very useful. The model exhibits experimentally-induced phosphorylated tau species, paired helical filament deposits, ubiquitinated inclusions, and protein oligomers, thus providing a valuable tool to study the associated sequelae underlying progressive cellular and synaptic compromise. In the absence of modulatory drugs, the protein accumulation events lead to microtubule destabilization, transport failure, and synaptic decline. When lysosomal modulators are administered to slices with pre-existing deposits, protein accumulations are reduced causing normalization of tau chemistry, restoration of tubulin structures and tubulin-binding proteins, and recovery of synaptic composition. Thus, positive modulators of the lysosomal system represent first-in-class drugs, providing a suitable strategy to enhance protein clearance, promote synaptic health, and slow the progression of proteinopathies.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Cathepsins/metabolism ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Lysosomes/metabolism ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/pathology ; Phosphorylation ; tau Proteins/metabolism
Chemical Substances	tau Proteins ; Cathepsins (EC 3.4.-)
Language	English
Publishing date	2009-10-16
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2205170-3
ISSN	1875-5828 ; 1567-2050
ISSN (online)	1875-5828
ISSN	1567-2050
DOI	10.2174/156720509789207903
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Article: Military blast-induced synaptic changes with distinct vulnerability may explain behavioral alterations in the absence of obvious brain damage.

Parisian, Catherine M / Georgevitch, Gregory / Bahr, Ben A

Journal of nature and science

2016 Volume 3, Issue 7

Abstract: Sadly many military veterans, who left home to serve their country honorably, return from service with permanent life-changing injuries. It is easy to remember our debt to those who have incurred such visible injuries, and all too easy to forget the ... ...

Abstract	Sadly many military veterans, who left home to serve their country honorably, return from service with permanent life-changing injuries. It is easy to remember our debt to those who have incurred such visible injuries, and all too easy to forget the invisible wounds that afflict so many of our military servicemen and women. Brain injuries can be invisible during initial medical evaluations and are often caused by military explosives that create blast shockwaves of varying intensity. One of the most common types of traumatic brain injury (TBI) linked to military service is blast-induced neurotrauma. To better understand this type of injury, a recently published study subjected rat brain slice cultures to detonations of RDX military explosives, resulting in reduced levels of specific synaptic markers. Such alterations have in fact been linked to depressive behavior, anxiety, and cognitive rigidity, and the blast-induced synaptic modifications may underlie the behavioral changes in those TBI sufferers who do not exhibit measurable brain damage. This research has the potential to improve diagnoses by identifying indicators of synapse integrity for the assessment of subtle synaptopathogenesis linked to blast-induced neurotrauma.
Language	English
Publishing date	2016-06-16
Publishing country	United States
Document type	Journal Article
ISSN	2377-2700
ISSN	2377-2700
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Article ; Online: Early Synaptic Alterations and Selective Adhesion Signaling in Hippocampal Dendritic Zones Following Organophosphate Exposure.

Farizatto, Karen L G / Almeida, Michael F / Long, Ronald T / Bahr, Ben A

Scientific reports

2019 Volume 9, Issue 1, Page(s) 6532

Abstract: Organophosphates account for many of the world's deadliest poisons. They inhibit acetylcholinesterase causing cholinergic crises that lead to seizures and death, while survivors commonly experience long-term neurological problems. Here, we treated brain ... ...

Abstract	Organophosphates account for many of the world's deadliest poisons. They inhibit acetylcholinesterase causing cholinergic crises that lead to seizures and death, while survivors commonly experience long-term neurological problems. Here, we treated brain explants with the organophosphate compound paraoxon and uncovered a unique mechanism of neurotoxicity. Paraoxon-exposed hippocampal slice cultures exhibited progressive declines in synaptophysin, synapsin II, and PSD-95, whereas reduction in GluR1 was slower and NeuN and Nissl staining showed no indications of neuronal damage. The distinctive synaptotoxicity was observed in dendritic zones of CA1 and dentate gyrus. Interestingly, declines in synapsin II dendritic labeling correlated with increased staining for β1 integrin, a component of adhesion receptors that regulate synapse maintenance and plasticity. The paraoxon-induced β1 integrin response was targeted to synapses, and the two-fold increase in β1 integrin was selective as other synaptic adhesion molecules were unchanged. Additionally, β1 integrin-cofilin signaling was triggered by the exposure and correlations were found between the extent of synaptic decline and the level of β1 integrin responses. These findings identified organophosphate-mediated early and lasting synaptotoxicity which can explain delayed neurological dysfunction later in life. They also suggest that the interplay between synaptotoxic events and compensatory adhesion responses influences neuronal fate in exposed individuals.
MeSH term(s)	Animals ; Antigens, Nuclear/metabolism ; Cholinesterase Inhibitors/pharmacology ; Dendrites/drug effects ; Dendrites/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Environmental Exposure ; Hippocampus/drug effects ; Hippocampus/metabolism ; Integrin beta1/metabolism ; Nerve Tissue Proteins/metabolism ; Neural Cell Adhesion Molecules/metabolism ; Organophosphates/toxicity ; Paraoxon/toxicity ; Rats ; Signal Transduction/drug effects ; Synapses/drug effects ; Synapses/pathology ; Synapsins/metabolism
Chemical Substances	Antigens, Nuclear ; Cholinesterase Inhibitors ; Disks Large Homolog 4 Protein ; Integrin beta1 ; Nerve Tissue Proteins ; Neural Cell Adhesion Molecules ; Organophosphates ; Rbfox3 protein, rat ; Synapsins ; Paraoxon (Q9CX8P80JW)
Language	English
Publishing date	2019-04-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-42934-z
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Article ; Online: Abnormal response of distal Schwann cells to denervation in a mouse model of motor neuron disease.

Carrasco, Dario I / Bahr, Ben A / Seburn, Kevin L / Pinter, Martin J

Experimental neurology

2016 Volume 278, Page(s) 116–126

Abstract: In several animal models of motor neuron disease, degeneration begins in the periphery. Clarifying the possible role of Schwann cells remains a priority. We recently showed that terminal Schwann cells (TSCs) exhibit abnormalities in postnatal mice that ... ...

Abstract	In several animal models of motor neuron disease, degeneration begins in the periphery. Clarifying the possible role of Schwann cells remains a priority. We recently showed that terminal Schwann cells (TSCs) exhibit abnormalities in postnatal mice that express mutations of the SOD1 enzyme found in inherited human motor neuron disease. TSC abnormalities appeared before disease-related denervation commenced and the extent of TSC abnormality at P30 correlated with the extent of subsequent denervation. Denervated neuromuscular junctions (NMJs) were also observed that lacked any labeling for TSCs. This suggested that SOD1 TSCs may respond differently than wildtype TSCs to denervation which remain at denervated NMJs for several months. In the present study, the response of SOD1 TSCs to experimental denervation was examined. At P30 and P60, SC-specific S100 labeling was quickly lost from SOD1 NMJs and from preterminal regions. Evidence indicates that this loss eventually becomes complete at most SOD1 NMJs before reinnervation occurs. The loss of labeling was not specific for S100 and did not depend on loss of activity. Although some post-denervation labeling loss occurred at wildtype NMJs, this loss was never complete. Soon after denervation, large cells appeared near SOD1 NMJ bands which colabeled for SC markers as well as for activated caspase-3 suggesting that distal SOD1 SCs may experience cell death following denervation. Denervated SOD1 NMJs viewed 7 days after denervation with the electron microscope confirmed the absence of TSCs overlying endplates. These observations demonstrate that SOD1 TSCs and distal SCs respond abnormally to denervation. This behavior can be expected to hinder reinnervation and raises further questions concerning the ability of SOD1 TSCs to support normal functioning of motor terminals.
MeSH term(s)	Age Factors ; Animals ; Antigens, Differentiation/metabolism ; Disease Models, Animal ; Gene Expression Regulation/genetics ; Gene Expression Regulation/physiology ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Neuron Disease/genetics ; Motor Neuron Disease/pathology ; Muscle Denervation/methods ; Mutation/genetics ; Nerve Regeneration/physiology ; Neuromuscular Junction/metabolism ; Neuromuscular Junction/pathology ; Neuromuscular Junction/ultrastructure ; Receptor, Nerve Growth Factor/metabolism ; Receptors, Cholinergic/metabolism ; S100 Proteins/metabolism ; Schwann Cells/metabolism ; Schwann Cells/pathology ; Sciatic Neuropathy/metabolism ; Sciatic Neuropathy/pathology ; Superoxide Dismutase/genetics
Chemical Substances	Antigens, Differentiation ; Receptor, Nerve Growth Factor ; Receptors, Cholinergic ; S100 Proteins ; monocyte-macrophage differentiation antigen ; SOD1 G93A protein (EC 1.15.1.1) ; Superoxide Dismutase (EC 1.15.1.1)
Language	English
Publishing date	2016-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2016.02.002
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Article ; Online: Aβ42-mediated proteasome inhibition and associated tau pathology in hippocampus are governed by a lysosomal response involving cathepsin B: Evidence for protective crosstalk between protein clearance pathways.

Farizatto, Karen L G / Ikonne, Uzoma S / Almeida, Michael F / Ferrari, Merari F R / Bahr, Ben A

PloS one

2017 Volume 12, Issue 8, Page(s) e0182895

Abstract: Impaired protein clearance likely increases the risk of protein accumulation disorders including Alzheimer's disease (AD). Protein degradation through the proteasome pathway decreases with age and in AD brains, and the Aβ42 peptide has been shown to ... ...

Abstract	Impaired protein clearance likely increases the risk of protein accumulation disorders including Alzheimer's disease (AD). Protein degradation through the proteasome pathway decreases with age and in AD brains, and the Aβ42 peptide has been shown to impair proteasome function in cultured cells and in a cell-free model. Here, Aβ42 was studied in brain tissue to measure changes in protein clearance pathways and related secondary pathology. Oligomerized Aβ42 (0.5-1.5 μM) reduced proteasome activity by 62% in hippocampal slice cultures over a 4-6-day period, corresponding with increased tau phosphorylation and reduced synaptophysin levels. Interestingly, the decrease in proteasome activity was associated with a delayed inverse effect, >2-fold increase, regarding lysosomal cathepsin B (CatB) activity. The CatB enhancement did not correspond with the Aβ42-mediated phospho-tau alterations since the latter occurred prior to the CatB response. Hippocampal slices treated with the proteasome inhibitor lactacystin also exhibited an inverse effect on CatB activity with respect to diminished proteasome function. Lactacystin caused earlier CatB enhancement than Aβ42, and no correspondence was evident between up-regulated CatB levels and the delayed synaptic pathology indicated by the loss of pre- and postsynaptic markers. Contrasting the inverse effects on the proteasomal and lysosomal pathways by Aβ42 and lactacystin, such were not found when CatB activity was up-regulated two-fold with Z-Phe-Ala-diazomethylketone (PADK). Instead of an inverse decline, proteasome function was increased marginally in PADK-treated hippocampal slices. Unexpectedly, the proteasomal augmentation was significantly pronounced in Aβ42-compromised slices, while absent in lactacystin-treated tissue, resulting in >2-fold improvement for nearly complete recovery of proteasome function by the CatB-enhancing compound. The PADK treatment also reduced Aβ42-mediated tau phosphorylation and synaptic marker declines, corresponding with the positive modulation of both proteasome activity and the lysosomal CatB enzyme. These findings indicate that proteasomal stress contributes to AD-type pathogenesis and that governing such pathology occurs through crosstalk between the two protein clearance pathways.
MeSH term(s)	Acetylcysteine/analogs & derivatives ; Acetylcysteine/pharmacology ; Amyloid beta-Peptides/metabolism ; Animals ; Cathepsin B/metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/pathology ; Lysosomes/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Peptide Fragments/metabolism ; Phosphorylation/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Rats, Sprague-Dawley ; Synaptophysin/metabolism ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; Cysteine Proteinase Inhibitors ; Peptide Fragments ; Synaptophysin ; amyloid beta-protein (1-42) ; tau Proteins ; lactacystin (133343-34-7) ; Cathepsin B (EC 3.4.22.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2017-08-10
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0182895
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Article ; Online: Excitotoxic stimulation activates distinct pathogenic and protective expression signatures in the hippocampus.

Caba, Ebru / Sherman, Marcus D / Farizatto, Karen L G / Alcira, Britney / Wang, Hsin-Wei / Giardina, Charles / Shin, Dong-Guk / Sandefur, Conner I / Bahr, Ben A

Journal of cellular and molecular medicine

2021 Volume 25, Issue 18, Page(s) 9011–9027

Abstract: Excitotoxic events underlying ischaemic and traumatic brain injuries activate degenerative and protective pathways, particularly in the hippocampus. To understand opposing pathways that determine the brain's response to excitotoxicity, we used ... ...

Abstract	Excitotoxic events underlying ischaemic and traumatic brain injuries activate degenerative and protective pathways, particularly in the hippocampus. To understand opposing pathways that determine the brain's response to excitotoxicity, we used hippocampal explants, thereby eliminating systemic variables during a precise protocol of excitatory stimulation. N-methyl-d-aspartate (NMDA) was applied for 20 min and total RNA isolated one and 24 h later for neurobiology-specific microarrays. Distinct groups of genes exhibited early vs. delayed induction, with 63 genes exclusively reduced 24-h post-insult. Egr-1 and NOR-1 displayed biphasic transcriptional modulation: early induction followed by delayed suppression. Opposing events of NMDA-induced genes linked to pathogenesis and cell survival constituted the early expression signature. Delayed degenerative indicators (up-regulated pathogenic genes, down-regulated pro-survival genes) and opposing compensatory responses (down-regulated pathogenic genes, up-regulated pro-survival genes) generated networks with temporal gene profiles mirroring coexpression network clustering. We then used the expression profiles to test whether NF-κB, a potent transcription factor implicated in both degenerative and protective pathways, is involved in the opposing responses. The NF-κB inhibitor MG-132 indeed altered NMDA-mediated transcriptional changes, revealing components of opposing expression signatures that converge on the single response element. Overall, this study identified counteracting avenues among the distinct responses to excitotoxicity, thereby suggesting multi-target treatment strategies and implications for predictive medicine.
MeSH term(s)	Animals ; Brain Injuries, Traumatic/therapy ; Gene Expression Regulation/drug effects ; Hippocampus/drug effects ; N-Methylaspartate/administration & dosage ; N-Methylaspartate/pharmacology ; NF-kappa B/metabolism ; Protective Agents/administration & dosage ; Protective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley
Chemical Substances	NF-kappa B ; Protective Agents ; N-Methylaspartate (6384-92-5)
Language	English
Publishing date	2021-08-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.16864
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