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PubMed: 30126037

Title
Tau protein aggregation is associated with cellular senescence in the brain.
Journal
Aging cell
Volume
17
Issue
None
Pages
e12840
Date
2018-12-01
Authors
Sickora KR | Orr ME | Thompson CS | Baeuerle E | Valentine JM | Shen Q | Musi N

Evidence c9d080f2a4
JSON

In 15-month-old mice with heavy Abeta deposition and phosphorylated tau, but lacking NFT pathology (Orr et al., 2014), Cdkn2a expression was not elevated (Figure 4e). These data indicate that Cdkn2a expression was neither a response to general protein accumulation, nor to pre-NFT tau pathology, but instead required the presence of NFTs

a(CHEBI:"amyloid-beta") causesNoChange p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt, pmod(Ph)) causesNoChange p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence f90c96f77d
JSON

Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada et al., 1992), yet mechanisms mediating tau toxicity are poorly understood

a(GO:"neurofibrillary tangle") decreases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(GO:"neurofibrillary tangle") increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 1ca60603cf
JSON

NFT containing neurons upregulated genes involved in cell survival and viability, inflammation, cell cycle progression and molecular transport and downregulated apoptosis, necrosis and cell death pathways (Figure 1a). NFkB, a pro-survival master transcriptional regulator of inflammation, was the highest predicted upstream regulator of the NFT-gene expression profile. In agreement with inflammatory activation, other predicted upstream regulators included IFNG, TNF, TLR4, IL1B and CXCL1 (Figure 1b)

a(GO:"neurofibrillary tangle") decreases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases bp(MESH:"Cell Survival") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases bp(GO:"cell cycle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") decreases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") decreases path(MESH:Necrosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(HGNC:NFKB1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(HGNC:IFNG) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(HGNC:TNF) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(HGNC:TLR4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases p(HGNC:CXCL1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 452fd46da7
JSON

Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice

a(GO:"neurofibrillary tangle") positiveCorrelation p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") association p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

p(MGI:Cdkn2a) association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

p(MGI:Cdkn2a) positiveCorrelation path(HP:"Cerebral atrophy") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

p(MGI:Cdkn2a) positiveCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

path(HP:"Cerebral atrophy") positiveCorrelation p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

Evidence 5ce421d221
JSON

Consistent with NFTs from human AD, mouse NFTs also caused significant activation scores for IFNG, TNF, IL-1B, as well as enrichment in other senescence associated JAK, STAT, CDKN2A and BCL2 predicted upstream regulators (Figure 1c) indicating translational relevance for using tauNFT mice to explore our hypothesis

a(GO:"neurofibrillary tangle") increases act(p(MGI:Cdkn2a)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases act(p(MGI:Ifng)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases act(p(MGI:Tnf)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases act(p(MGI:Il1b)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases act(p(MGI:Jak1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases act(p(MGI:Stat1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

a(GO:"neurofibrillary tangle") increases act(p(MGI:Bcl2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 8220defaa1
JSON

Cdkn2a gene expression increased significantly during this age interval, and at 28 months of age tauWT Cdkn2a expression was similar to that of 16-month-old tauNFT mice (Figure 4c)

a(GO:"neurofibrillary tangle") increases p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence 1c22f25a14
JSON

Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration

a(GO:"neurofibrillary tangle") association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

Evidence c43cd42c8a
JSON

Similarly, elevated expression of the cyclin dependent kinase inhibitor 2a, Cdkn2a, is one of the most robust markers of cellular senescence, and its protein product, p16INK4A, co-localizes with NFTs in human AD (Arendt et al., 1996)

a(GO:"neurofibrillary tangle") association p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

p(HGNC:CDKN2A) association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 3ef1fdb135
JSON

Consistent with the results from transgenic mice, CDKN2A was upregulated in PSP brains (P = 0.0415, Figure 4g) and expression correlated with NFT deposition, specifically in the parietal lobe (ANOVA, P = 0.0008; Kendall’s Tau rank correlation P = 0.059, Figure 4h)

a(GO:"neurofibrillary tangle") positiveCorrelation p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

p(HGNC:CDKN2A) positiveCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

p(HGNC:CDKN2A) positiveCorrelation path(MESH:"Supranuclear Palsy, Progressive") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") positiveCorrelation p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

Evidence e27b10e7a0
JSON

Collectively, these findings led us to conclude that NFTs were directly linked to senescence-associated Cdkn2a upregulation, which in turn was a strong predictor of neurodegeneration and cognitive decline

a(GO:"neurofibrillary tangle") increases p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

bp(HP:Neurodegeneration) association p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

p(HGNC:CDKN2A) association bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

p(HGNC:CDKN2A) association path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Cognitive Dysfunction") association p(HGNC:CDKN2A) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Parietal Lobe
MeSH
Supranuclear Palsy, Progressive

Evidence ff4be5ab78
JSON

We found a significant genotype main effect for oxygen flux in both cortex and hippocampus, indicating that global respiratory capacity was impaired in NFT containing brain regions (P < 0.0001; Figure 3), an effect primarily driven by CI+CII respiration coupled to ATP production (cortex: P = 0.0034; hippocampus: P = 0.0215; Figure 2g and h, respectively), and uncoupled or maximum respiratory capacity (cortex: P = 0.0248; hippocampus: P = 0.0261; Figure 3g and h, respectively)

a(GO:"neurofibrillary tangle") decreases bp(GO:"oxygen transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

bp(GO:"oxidative phosphorylation") decreases bp(GO:"oxygen transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence eae8cf1dae
JSON

NFTs are highly correlated with the rate of ventricular enlargement, an indicator of brain atrophy and hallmark of AD pathology (Silbert et al., 2003)

a(GO:"neurofibrillary tangle") association path(MESH:"Hypertrophy, Right Ventricular") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(GO:"neurofibrillary tangle") association path(MESH:"Hypertrophy, Left Ventricular") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(GO:"neurofibrillary tangle") association path(HP:"Brain atrophy") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(HP:"Brain atrophy") association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Hypertrophy, Left Ventricular") association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Hypertrophy, Right Ventricular") association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 263ff302ab
JSON

Further, SA beta-gal reactive cells were observed even in very young mice (1-month-old) and the number of SA beta-gal reactive cells was positively correlated with brain mass (R2: 0.4852, P = 0.0039 Figure S3)

a(HP:brain) positiveCorrelation p(MGI:Glb1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Glb1) positiveCorrelation a(HP:brain) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 57a6c2a3cf
JSON

Citrate synthase activity is a surrogate marker of total mitochondrial content/mass, and was similar across genotypes and brain regions (Figure 3i) suggesting that the defects in cellular respiration were due to altered mitochondrial quality, not content/mass

act(a(MESH:Mitochondria)) association bp(GO:"cellular respiration") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

bp(GO:"cellular respiration") association act(a(MESH:Mitochondria)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence 3750c95a2a
JSON

Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction

bp(GO:"cell cycle") association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") association bp(GO:"cell cycle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases bp(MESH:"Cell Survival") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases bp(GO:"tissue remodeling") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") decreases bp(GO:"metabolic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease

Evidence 6884c73761
JSON

This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, metabolic dysfunction and disruption to surrounding tissue to the secretion of toxic molecules (Childs et al., 2016)

bp(GO:"cellular senescence") increases bp(MESH:"Cell Survival") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases bp(GO:"tissue remodeling") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") decreases bp(GO:"metabolic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases bp(GO:"cell cycle arrest") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") decreases sec(a(MESH:Immunotoxins)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Alzheimer Disease

Evidence e6998aaab8
JSON

NFkB regulates the pro-survival, pro-inflammatory SASP gene expression profile characteristic of cellular senescence (Salminen & Kaarniranta, 2011)

bp(GO:"cellular senescence") association bp(MESH:"Cell Survival") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") association bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

bp(GO:"inflammatory response") association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

bp(MESH:"Cell Survival") association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

act(p(MGI:Nfkb1)) increases bp(MESH:"Cell Survival") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

act(p(MGI:Nfkb1)) increases bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 2b241a4936
JSON

Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss and ventricular enlargement

bp(GO:"cellular senescence") increases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases path(MESH:"Hypertrophy, Right Ventricular") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases path(MESH:"Hypertrophy, Left Ventricular") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

Evidence a0ea675a42
JSON

Experimental data from various studies indicate that tau pathology may be associated with cellular senescence, a fundamental aging mechanism shown to contribute to several chronic diseases (recent review Kirkland and Tchkonia, 2017)

bp(GO:"cellular senescence") association path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:Tauopathies) association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Alzheimer Disease

Evidence d89bf1c9eb
JSON

Senescence-inducing stressors often inflict DNA-damage that drives production of the SASP (Rodier et al., 2009)

bp(GO:"cellular senescence") increases bp(MESH:"DNA Damage") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 72ee914b50
JSON

The cell cycle protein p21, encoded by Cdkn1a, is upregulated in many senescent cell types and has been associated with DNA damage during neuronal aging (Jurk et al., 2012)

bp(GO:"cellular senescence") association bp(MESH:"DNA Damage") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

bp(GO:"cellular senescence") increases p(MGI:Cdkn1a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

bp(MESH:"DNA Damage") association bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 06071c4a2f
JSON

Mitochondrial dysfunction is obligatory for SASP production and cellular senescence (Correia-Melo et al., 2016; Hutter et al., 2004)

bp(GO:"cellular senescence") increases bp(HBP:HBP00037) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 089db82ad7
JSON

Aberrant cerebral blood flow is a functional defect that occurs in AD and tauNFT mice, and is closely associated with cognitive impairment (Wells et al., 2015)

bp(MESH:"Cerebrovascular Circulation") association p(MGI:Mapt, var("p.Pro301Leu")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

bp(MESH:"Cerebrovascular Circulation") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

bp(MESH:"Cerebrovascular Circulation") association path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(MGI:Mapt, var("p.Pro301Leu")) association bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Alzheimer Disease") association bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Cognitive Dysfunction") association bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence c7fa0fb320
JSON

Consistent with senescent cell removal, intermittent DQ treatment significantly reduced the number of NFT-containing cortical neurons (P < 0.0001, 5% reduction; Figure 5a,b)

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 9d9802bc22
JSON

The DQ-dependent reduction in cortical NFTs corresponded with decreased ventricular volume pathology (28% decrease, P = 0.05, Figure 5d, f) and a reduction in cortical brain atrophy (compared to controls: P = 0.0092 and P = 0.0274, vehicle and DQ, respectively; Figure S5a)

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases path(HP:"Brain atrophy") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases path(HP:"cardiac ventricle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 0e55422078
JSON

The astrocyte protein GFAP was unchanged, while microglia Iba1 expression was elevated (Iba1: 40%, P = 0.0013; Figure S6b-d) suggesting that DQ-mediated neuroprotection and decreased SASP was not derived from a reduction in pro-inflammatory glia (astrocytes or microglia) but instead associated with fewer NFT-containing neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) increases p(MGI:Aif1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) increases bp(MESH:Neuroprotection) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 810d458008
JSON

Relative to the existing neuronal population at this advanced age, gene expression of the NFT-associated senescence gene array was reduced by DQ (P = 0.0006; Figure S6a)

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 10f4227c23
JSON

However, tauNFT-Mapt0/0 mice treated with DQ did not display WMH volumes statistically different than control mice (P = 0.2458; Figure S5b, c)

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases path(HP:"Hyperintensity of cerebral white matter on MRI") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 985531e6d6
JSON

DQ improved cerebral blood flow in tauNFT Mapt0/0 mice such that cerebral blood flow was no longer statistically different from controls (Figure S5d, e)

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) decreases bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Tauopathies

Evidence 3fa6183730
JSON

DQ-treated mice expressed significantly higher levels of neuronal proteins (NeuN: 25%, synaptophysin: 40.8%; PSD95: 38.5%; P < 0.05; Figure 5f-i)

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) increases p(MGI:Syp) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) increases p(MGI:Rbfox3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

composite(a(CHEBI:"dasatinib (anhydrous)"), a(CHEBI:quercetin)) increases p(MGI:Dlg4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence a817a69bb5
JSON

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others

p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT) association path(MESH:"Supranuclear Palsy, Progressive") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT) association path(MESH:"Brain Injuries, Traumatic") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Brain Injuries, Traumatic") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Supranuclear Palsy, Progressive") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 4bc1381721
JSON

Further, when plotted against brain weight, Cdkn2a expression was a strong predictor of brain atrophy across mouse lines (P < 0.0001, R2 = 0.5615; Figure 4f)

p(MGI:Cdkn2a) positiveCorrelation path(HP:"Brain atrophy") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

path(HP:"Brain atrophy") positiveCorrelation p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence 18d5af744b
JSON

TauNFT mouse brains displayed significantly elevated histone γ-H2ax, a sensitive marker of both double-stranded DNA breaks and cellular senescence (Sedelnikova et al., 2004) (P = 0.0056; Figure 1d-e)

p(MGI:H2afx) biomarkerFor bp(MESH:"DNA Breaks, Double-Stranded") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:H2afx) biomarkerFor bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:H2afx) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 1495e4aa74
JSON

However, genetically ablating endogenous mouse tau (microtubule associated protein tau, Mapt) reduces NFT pathology and neurodegeneration in tauNFT mice (tauNFT-Mapt0/0) (Wegmann et al., 2015)

p(MGI:Mapt) increases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt) increases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence 0f8d65f693
JSON

The reduced tau pathology corresponded with 60% lower Cdkn2a expression (P = 0.0041, Figure 4a), decreased SASP (Figure S4) and decreased brain atrophy (tauNFT-Mapt0/0: 0.4058 ± 0.009 versus age-matched tauNFT Maptwt/wt: 0.3451 ± 0.0116; 17.5% difference, P = 0.0143, Figure 4b)

p(MGI:Mapt) increases p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt) increases bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt) increases path(HP:"Brain atrophy") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence dedeae1276
JSON

TauNFT brains expressed 3-fold higher Cdkn1a than control mice (P = 0.0178, Figure 1f), which was replicated in a separate mouse cohort (P = 0.0086, Figure S1f)

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Cdkn1a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 8091e10067
JSON

Moreover, Cdkn2a was expressed at levels 2.7- and 2.6-fold higher in tauNFT than CTL and tauWT, respectively (P = 0.0303 and P = 0.0352, respectively; Figure 1g); this effect was replicated in an independent mouse cohort (P = 0.0016, Figure S1g)

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Cdkn2a) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence af290ffc7d
JSON

Consistent with the transcriptomic profile in human NFT-bearing neurons and mouse brain tissue (Figure 1a-c), SASP genes were found to be upregulated in tauNFT brains, i.e., Il1b was 4- and 2-fold higher than CTL and tauWT, respectively; and Cxcl1 was 4-fold higher than both control genotypes; Tnfa was 13- and 8-fold higher than CTL and tauWT, respectively; Tlr4 was 3-fold higher than both control genotypes (Figure 2a-d)

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Cxcl1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Tlr4) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 068a3e0907
JSON

Consistent with NFkB pathway activation and the SASP profile, nuclear localized NFkB p65 was significantly increased in tauNFT brains (Figure 2e-f)

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:"NIK/NF-kappaB signaling") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Rela) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence e86f79b6d7
JSON

Examination of the gene that codes for the hydrolase enzyme, galactosidase beta 1 (Glb1), revealed that tauNFT mice expressed higher Glb1 gene expression than controls (Figure S3)

p(MGI:Mapt, var("p.Pro301Leu")) increases p(MGI:Glb1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease

Evidence 275f3809ce
JSON

TauNFT mice develop aggressive tauopathy with NFT formation in early life, and show a senescence-associated transcriptomic profile with NFT onset (Figure 1c)

p(MGI:Mapt, var("p.Pro301Leu")) increases path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(GO:"cellular senescence") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence dfa58e54c0
JSON

In brain tissue with tau pathology, cerebral blood flow was elevated in tauNFT Mapt0/0 vehicle-treated mice (21% whole brain, P = 0.045; cortex, 48.7%, P = 0.051, Figure S5d, e), and consistent with previous reports of tauNFT mice on a Mapt+/+ background (Wells et al., 2015)

p(MGI:Mapt, var("p.Pro301Leu")) increases bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Tauopathies

Evidence 4ba357d358
JSON

WMH is driven by cerebral small vessel disease, which causes chronic ischemia and increased risk of cognitive decline and dementia (reviewed, (Prins & Scheltens, 2015))

path(MESH:"Cerebral Small Vessel Diseases") increases path(HP:"Hyperintensity of cerebral white matter on MRI") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Cerebral Small Vessel Diseases") increases path(MESH:Ischemia) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Cerebral Small Vessel Diseases") increases path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

path(MESH:"Cerebral Small Vessel Diseases") increases path(MESH:Dementia) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 02ac4f741d
JSON

PSP is an age-associated tauopathy that clinically manifests as parkinsonism with additional motor abnormalities and cognitive dysfunction (Orr et al., 2017), and is neuropathologically defined by accumulation of four-repeat (4R) tau, NFTs, gliosis and neurodegeneration (Flament et al., 1991)

path(MESH:"Parkinsonian Disorders") association path(MESH:"Supranuclear Palsy, Progressive") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") increases a(HBP:HBP00045) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") increases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") increases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") increases path(MESH:Gliosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") increases path(MESH:"Motor Disorders") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") association path(MESH:"Parkinsonian Disorders") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") association path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:"Supranuclear Palsy, Progressive") increases path(MESH:"Cognitive Dysfunction") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

path(MESH:Tauopathies) association path(MESH:"Supranuclear Palsy, Progressive") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Supranuclear Palsy, Progressive

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.