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PubMed: 29758300

Title
Alzheimer's disease and the autophagic-lysosomal system.
Journal
Neuroscience letters
Volume
None
Issue
None
Pages
None
Date
2018-05-18
Authors
Sproul AA | Hernández N | Chung KM | Yu WH

Evidence 86f82e7c74
JSON

Under starvation or stress, TFEB translocates to the nucleus and binds the CRE element to promote expression of macroautophagy and lysosomal genes [88].

bp(GO:"cellular response to stress") increases tloc(p(HGNC:TFEB), fromLoc(GO:cytosol), toLoc(GO:nucleus)) View Subject | View Object

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bp(GO:"cellular response to stress") increases complex(p(HGNC:TFEB), p(INTERPRO:"cAMP response element binding (CREB) protein")) View Subject | View Object

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complex(p(HGNC:TFEB), p(INTERPRO:"cAMP response element binding (CREB) protein")) increases bp(GO:macroautophagy) View Subject | View Object

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complex(p(HGNC:TFEB), p(INTERPRO:"cAMP response element binding (CREB) protein")) increases a(GO:lysosome) View Subject | View Object

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path(MESH:Starvation) increases tloc(p(HGNC:TFEB), fromLoc(GO:cytosol), toLoc(GO:nucleus)) View Subject | View Object

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path(MESH:Starvation) increases complex(p(HGNC:TFEB), p(INTERPRO:"cAMP response element binding (CREB) protein")) View Subject | View Object

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Evidence f68b9c42e8
JSON

Protein clearance in animal models has been successfully demonstrated using several small molecules and drugs that enhance induction of macroautophagy reduces AD-relevant pathology, including rapamycin in 3xTGAD mice [32] and temsirolimus in P301S transgenic mice [156] and trehalose in APP/PS1 and P301S MAPT transgenic mice [157,158].

a(CHEBI:"alpha,alpha-trehalose") increases bp(GO:macroautophagy) View Subject | View Object

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a(CHEBI:Temsirolimus) increases bp(GO:macroautophagy) View Subject | View Object

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a(CHEBI:sirolimus) increases bp(GO:macroautophagy) View Subject | View Object

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Evidence 1d0e5284df
JSON

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32]

a(CHEBI:"amyloid-beta") positiveCorrelation act(complex(GO:"TOR complex")) View Subject | View Object

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a(CHEBI:"amyloid-beta") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

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a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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a(CHEBI:sirolimus) increases bp(GO:macroautophagy) View Subject | View Object

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bp(GO:macroautophagy) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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act(complex(GO:"TOR complex")) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence a836ae9b17
JSON

This inhibition of Aβ secretion during macroautophagy deficiency results in aberrant cytosolic accumulation of Aβ, which ultimately evokes neurodegeneration accompanied with memory loss.

sec(a(CHEBI:"amyloid-beta")) decreases path(HBP:Neurodegeneration) View Subject | View Object

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sec(a(CHEBI:"amyloid-beta")) increases bp(GO:memory) View Subject | View Object

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bp(GO:macroautophagy) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

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Evidence a2b48f2557
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Although exact relations remain unknown, it was reported that Aβ can induce a cascade that results in phosphorylation and subsequent deposition of TDP-43 in the cytosol [70]

a(CHEBI:"amyloid-beta") increases p(HGNC:TARDBP, pmod(Ph)) View Subject | View Object

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a(CHEBI:"amyloid-beta") increases p(HGNC:TARDBP) View Subject | View Object

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Annotations
MeSH
Cytosol

Evidence 6f78378ea2
JSON

Overexpression of PICALM in APP/PS1 mice substantially elevates Aβ levels, whereas knockdown reduces the Aβ plaque load, respectively [98]

a(CHEBI:"amyloid-beta") positiveCorrelation p(HGNC:PICALM) View Subject | View Object

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p(HGNC:PICALM) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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p(HGNC:PICALM) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

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Evidence b235a5f4e0
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Identified as a candidate susceptibility gene for AD by GWAS [116], reduced level of SORL1 has been consistently correlated with brain Aβ levels [118,119].

a(CHEBI:"amyloid-beta") negativeCorrelation p(HGNC:SORL1) View Subject | View Object

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p(HGNC:SORL1) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 710a37c2bc
JSON

Furthermore, presenilin-1, the most common mutation associated with early-onset familial AD (FAD), plays an essential role in calcium homeostasis and maintaining acidic lysosomal pH, with FAD-associated mutations disrupting calcium-dependent vATPase function in lysosomes [7,18–20]

a(CHEBI:"calcium ion") increases act(a(MESH:"Vacuolar Proton-Translocating ATPases")) View Subject | View Object

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bp(GO:"calcium ion homeostasis") association p(HGNC:PSEN1) View Subject | View Object

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bp(GO:"regulation of lysosomal lumen pH") association p(HGNC:PSEN1) View Subject | View Object

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p(HGNC:PSEN1) association bp(GO:"calcium ion homeostasis") View Subject | View Object

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p(HGNC:PSEN1) association bp(GO:"regulation of lysosomal lumen pH") View Subject | View Object

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p(HGNC:PSEN1, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:PSEN1, var("?")) decreases act(a(MESH:"Vacuolar Proton-Translocating ATPases")) View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HGNC:PSEN1, var("?")) View Subject | View Object

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Evidence 4ea7de51da
JSON

Methylene blue, a contrast agent that can reduce tau misfolding, has also been shown to induce macroautophagy, as indicated by elevated Beclin 1 and LC3-II levels and reduced tau and p62 levels in organotypic neuronal cultures and a mouse model of FTD [159]

a(CHEBI:"methylene blue") decreases p(HGNC:MAPT, pmod(HBP:misfolding)) View Subject | View Object

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a(CHEBI:"methylene blue") increases bp(GO:macroautophagy) View Subject | View Object

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a(CHEBI:"methylene blue") increases p(HGNC:BECN1) View Subject | View Object

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a(CHEBI:"methylene blue") increases p(HGNC:MAP1LC3B) View Subject | View Object

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a(CHEBI:"methylene blue") decreases p(HGNC:MAPT) View Subject | View Object

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a(CHEBI:"methylene blue") decreases p(HGNC:SQSTM1) View Subject | View Object

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Evidence 6b95a9cfd3
JSON

Sphingolipids are also strongly implicated in AD pathology, with upregulated levels of ceramide, a key component in sphingolipid metabolism, detected in the early phase of AD [80].

a(CHEBI:ceramide) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:ceramide) View Subject | View Object

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Evidence 50e657218e
JSON

Cellular cholesterol can directly impact the level of Aβ, as decreases in cholesterol levels inhibit the generation of Aβ peptides through direct modulation of γ-secretase activity [78,79].

a(CHEBI:cholesterol) increases a(MESH:"Amyloid beta-Peptides") View Subject | View Object

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a(CHEBI:cholesterol) regulates act(complex(GO:"gamma-secretase complex")) View Subject | View Object

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Evidence 95d72e5a43
JSON

Paclitaxel reversed Aβ-induced microtubule disruption and restored autophagosomal transport in neurons [161], while a similar compound, epothilone D/BMS-241027, reduced tauopathy and improved cognition in P301S transgenic mice [162] although the compound did not progress beyond Phase I clinical testing

a(CHEBI:epothilone) decreases path(MESH:Tauopathies) View Subject | View Object

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a(CHEBI:epothilone) increases bp(GO:cognition) View Subject | View Object

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a(CHEBI:paclitaxel) increases a(GO:microtubule) View Subject | View Object

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a(CHEBI:paclitaxel) increases tloc(a(GO:autophagosome), fromLoc(GO:"extracellular space"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 099ad72efa
JSON

In addition to their structural role in membranes, lipids are essential in the maintenance of cellular energy homeostasis as well as regulation of intracellular signaling pathways

a(CHEBI:lipid) regulates bp(GO:"energy homeostasis") View Subject | View Object

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a(CHEBI:lipid) regulates bp(GO:"intracellular signal transduction") View Subject | View Object

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Evidence 3ccbf5cf3c
JSON

Decreased triglyceride breakdown upon macroautophagy inhibition and impairment in macroautophagy by lipid supplementation demonstrates reciprocally interrelated regulation of autophagy and lipids [72]

a(CHEBI:lipid) regulates bp(GO:macroautophagy) View Subject | View Object

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bp(GO:macroautophagy) increases deg(a(CHEBI:triglyceride)) View Subject | View Object

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Evidence 4e0caebe0c
JSON

Lipid biology can also impact proteinopathy, with strong evidence that Aβ metabolism is modulated by lipids

a(CHEBI:lipid) regulates bp(GO:"amyloid-beta metabolic process") View Subject | View Object

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Evidence 1dde898580
JSON

In addition to the direct modulation of protein generation, lipids can also influence the levels of proteins through autophagic clearance; for instance, increasing lipid contents has been shown to impair autophagy [72].

a(CHEBI:lipid) negativeCorrelation bp(GO:autophagy) View Subject | View Object

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bp(GO:autophagy) negativeCorrelation a(CHEBI:lipid) View Subject | View Object

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Evidence 000492d901
JSON

For instance, rapamycin, an inhibitor of the Ser/Thr protein kinase mammalian target of rapamycin (mTOR), improves cognitive function and reduces Aβ in AD mouse model by enhancing autophagic flux [23].

a(CHEBI:sirolimus) decreases act(p(HGNC:MTOR)) View Subject | View Object

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a(CHEBI:sirolimus) increases bp(GO:cognition) View Subject | View Object

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a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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a(CHEBI:sirolimus) increases bp(GO:autophagy) View Subject | View Object

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Evidence b23d047703
JSON

Modulation of mTOR can influence the levels of tau, with upregulation increasing tau phosphorylation and accumulation by reducing autophagic clearance [87], and conversely, pharmacological treatment with rapamycin reducing tau levels and rescuing motor deficits in the Tau P301S mice [53]

a(CHEBI:sirolimus) decreases p(HGNC:MAPT) View Subject | View Object

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a(CHEBI:sirolimus) increases bp(GO:"motor behavior") View Subject | View Object

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bp(GO:autophagy) negativeCorrelation p(HGNC:MTOR) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:MTOR) View Subject | View Object

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p(HGNC:MTOR) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:MTOR) negativeCorrelation bp(GO:autophagy) View Subject | View Object

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Evidence d639aea648
JSON

The finding of reduced Aβ generation when conversion of sphingomyelin to ceramide is blocked further substantiates the crucial involvement of sphingolipids in Aβ metabolism through modulation of γ-secretase [81,82]

a(CHEBI:sphingolipid) regulates act(complex(GO:"gamma-secretase complex")) View Subject | View Object

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rxn(reactants(a(MESH:Sphingomyelins)), products(a(CHEBI:ceramide))) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 494d6a47a6
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For example, levels of Beclin 1, a key component of the class III type phosphoinositide 3-kinase/VPS34 complex essential to the pre-autophagosomal structure (PAS), has been suggested to be reduced in AD brains [16,17], with Rohn et al. demonstrating the cleavage of Beclin 1 by caspase-3 in the AD brain and colocalization of the cleaved product with NFTs [16].

a(GO:"neurofibrillary tangle") association p(HGNC:BECN1, frag("?")) View Subject | View Object

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Annotations
MeSH
Brain

p(HGNC:BECN1) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

p(HGNC:BECN1, frag("?")) association a(GO:"neurofibrillary tangle") View Subject | View Object

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MeSH
Brain

p(HGNC:CASP3) increases p(HGNC:BECN1, frag("?")) View Subject | View Object

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MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:BECN1) View Subject | View Object

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MeSH
Brain

Evidence 5f989971aa
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Other studies have also demonstrated the accumulation of autolysosomes in the AD brain and experimentally when lysosomal proteolysis is compromised via genetic knockdown of specific cathepsins or use of pharmacological inhibition of lysosomes [2,3,15]

a(GO:autolysosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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MeSH
Brain

bp(GO:"lysosomal protein catabolic process") decreases a(GO:autolysosome) View Subject | View Object

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:autolysosome) View Subject | View Object

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Annotations
MeSH
Brain

Evidence 80260d6ddb
JSON

Mitochondria are instrumental in the regulation of energy metabolism, and impairment in mitochondrial function has been implicated in the pathogenesis of AD, leading to the mitochondrial cascade hypothesis of AD [121].

a(GO:mitochondrion) regulates bp(GO:"energy homeostasis") View Subject | View Object

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path(HBP:"mitochondrial dysfunction") increases path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence a7308cffd4
JSON

Tau aggregates can be targeted by two protein clearance pathways, the UPS and the A-LS, with the latter pathway encompassing microautophagy,CMA and macroautophagy.

a(HBP:"Tau aggregates") association bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

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a(HBP:"Tau aggregates") association bp(GO:autophagy) View Subject | View Object

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bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") association a(HBP:"Tau aggregates") View Subject | View Object

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bp(GO:autophagy) association a(HBP:"Tau aggregates") View Subject | View Object

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Evidence b3fbcdad3d
JSON

Furthermore, the membrane bilayer lipid can influence protein aggregation and subsequent tau pathology, with recent studies showing that tau binds to the membrane, which has subsequent effects on the formation of fibrillary tau aggregates [85,86].

a(HBP:"Tau aggregates") association complex(a(MESH:"Lipid Bilayers"), p(HGNC:MAPT)) View Subject | View Object

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complex(a(MESH:"Lipid Bilayers"), p(HGNC:MAPT)) association a(HBP:"Tau aggregates") View Subject | View Object

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Evidence 714e4c204a
JSON

While AD is generally considered a disorder with two proteinopathies, other protein aggregates are also seen in AD, like α-synuclein

a(HBP:"alpha-synuclein aggregates") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(HBP:"alpha-synuclein aggregates") View Subject | View Object

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Evidence 2096813afc
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First identified as a nonamyloid component of Aβ plaques in the AD brain, α-synuclein aggregates are detected in the majority of the brains of patients with AD [56,57].

a(HBP:"alpha-synuclein aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"alpha-synuclein aggregates") View Subject | View Object

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Annotations
MeSH
Brain

Evidence a44a679491
JSON

Misfolded α-synuclein proteins form insoluble oligomers, which in turn lead to the cascade of pathogenic neurotoxicity-induced responses such as neuroinflammation and cell death [55]

a(HBP:"alpha-synuclein oligomers") increases path(HBP:neuroinflammation) View Subject | View Object

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a(HBP:"alpha-synuclein oligomers") increases bp(GO:"cell death") View Subject | View Object

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p(HGNC:SNCA, pmod(HBP:misfolding)) increases a(HBP:"alpha-synuclein oligomers") View Subject | View Object

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Evidence 610778d113
JSON

The presence of aberrant protein aggregates is common to neurodegenerative diseases

a(HBP:"protein aggregates") positiveCorrelation path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") positiveCorrelation a(HBP:"protein aggregates") View Subject | View Object

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Evidence 59891841fa
JSON

Defective chaperone-mediated autophagy (CMA), a type of autophagy that targets proteins with a specific KFERQ-like motif recognizable to its chaperones, plays a significant role in aggregate formation of disease-related proteins [28].

bp(GO:"chaperone-mediated autophagy") decreases a(HBP:"protein aggregates") View Subject | View Object

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Evidence c529275ef2
JSON

Evidence suggests that CMA can degrade tau via the chaperone heat shock cognate of 70 kDa (Hsc70), which recognizes KFERQ-like motifs and transfers its substrates via LAMP-2 into the lysosome [47]

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:MAPT)) View Subject | View Object

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composite(p(HGNC:HSPA8), p(HGNC:LAMP2)) increases tloc(p(HGNC:MAPT), fromLoc(GO:cytosol), toLoc(GO:lysosome)) View Subject | View Object

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p(HGNC:HSPA8) increases deg(p(HGNC:MAPT)) View Subject | View Object

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Evidence 6aa056ffb8
JSON

Cuervo et al. have revealed a distinct interaction of wild-type and mutant α-synuclein proteins with CMA [64]

p(HGNC:SNCA) association bp(GO:"chaperone-mediated autophagy") View Subject | View Object

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bp(GO:"chaperone-mediated autophagy") association p(HGNC:SNCA) View Subject | View Object

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bp(GO:"chaperone-mediated autophagy") association p(HGNC:SNCA, var("?")) View Subject | View Object

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p(HGNC:SNCA, var("?")) association bp(GO:"chaperone-mediated autophagy") View Subject | View Object

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Evidence 90b1a9a843
JSON

While wild-type α-synuclein protein efficiently clears via CMA, the pathogenic A53T and A30P variants remain bound to LAMP-2, blocking lysosomal degradation by preventing binding of other substrate complexes to the receptor [64].

bp(GO:"chaperone-mediated autophagy") increases deg(p(HGNC:SNCA)) View Subject | View Object

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complex(p(HGNC:LAMP2), p(HGNC:SNCA, var("p.Ala30Pro"))) decreases bp(GO:"lysosomal protein catabolic process") View Subject | View Object

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complex(p(HGNC:LAMP2), p(HGNC:SNCA, var("p.Ala53Thr"))) decreases bp(GO:"lysosomal protein catabolic process") View Subject | View Object

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Evidence 2d6a7f1ba5
JSON

Such evidence of lysosomal proteolytic failure in AD brain further strengthens the concept that impaired macroautophagy in AD is a critical event

bp(GO:"lysosomal protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

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Annotations
MeSH
Brain

Evidence 9d401ad5c0
JSON

Even early autophagic activation may become impaired due to progressively diminishing lysosomal clearance of substrates.

bp(GO:"lysosomal protein catabolic process") positiveCorrelation bp(GO:autophagy) View Subject | View Object

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bp(GO:autophagy) positiveCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

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Evidence cb687d8942
JSON

With neurons profoundly relying on macroautophagy for clearance of toxic protein aggregates, impairment in the proteolytic systems ultimately results in progressive neuronal death, a common feature in several neurodegenerative diseases [27].

bp(GO:"neuron death") association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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bp(GO:macroautophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

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bp(GO:proteolysis) decreases bp(GO:"neuron death") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association bp(GO:"neuron death") View Subject | View Object

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Evidence 214ffcb092
JSON

Impairment in the UPS is cardinal to the development of neurodegeneration, in part because of its reciprocal interplay with protein aggregation

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(HBP:Neurodegeneration) View Subject | View Object

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path(HBP:Neurodegeneration) negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

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Evidence 08f6d176a4
JSON

For instance, phosphorylated insoluble tau proteins dampen 26S proteasome activity, while activation of the UPS attenuates tauopathy [27]

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") decreases path(MESH:Tauopathies) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph)) decreases act(complex(GO:"proteasome complex")) View Subject | View Object

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Evidence 86cc97c128
JSON

These experimental differences may be attributed to the intricate interplay between the UPS and autophagy, as α-synuclein is degraded by both proteolytic systems [62,63].

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(p(HGNC:SNCA)) View Subject | View Object

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bp(GO:autophagy) increases deg(p(HGNC:SNCA)) View Subject | View Object

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Evidence 59915fbc8d
JSON

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux

bp(GO:autophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") increases complex(a(GO:autophagosome), a(HBP:"dystrophic neurite")) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:autophagy) View Subject | View Object

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Evidence 05bb0152e7
JSON

Although the UPS is accountable for the degradation of up to 80–90% of proteins, misfolded proteins and aggregates are too large to be processed through the proteasome barrel and can impede UPS function by physical occlusion, leaving autophagic-lysosomal breakdown as the only effective pathway to clear these proteins [25,26]

bp(GO:autophagy) increases deg(p(MESH:Proteins, pmod(HBP:misfolding))) View Subject | View Object

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bp(GO:autophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

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Evidence b8b6c00c34
JSON

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45].

bp(GO:autophagy) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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complex(GO:"proteasome complex") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph)) association complex(GO:"proteasome complex") View Subject | View Object

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p(HGNC:MAPT, pmod(Ph)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:MAPT, pmod(Ph)) association bp(GO:autophagy) View Subject | View Object

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Evidence eb16622129
JSON

TFEB has been shown to effectively clear phosphorylated tau proteins through A-LS, resulting in ameliorated neuronal loss and neuroinflammation, as well as improved cognitive performance [89].

bp(GO:autophagy) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

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p(HGNC:TFEB) increases bp(GO:autophagy) View Subject | View Object

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p(HGNC:TFEB) increases deg(p(HGNC:MAPT, pmod(Ph))) View Subject | View Object

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deg(p(HGNC:MAPT, pmod(Ph))) decreases bp(GO:"neuron death") View Subject | View Object

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deg(p(HGNC:MAPT, pmod(Ph))) decreases path(HBP:neuroinflammation) View Subject | View Object

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deg(p(HGNC:MAPT, pmod(Ph))) increases bp(GO:cognition) View Subject | View Object

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Evidence 9ad5382e61
JSON

Decreased autophagy in the diseased brain may contribute to aberrant lipid accumulation that occurs along with an increased incidence of the metabolic syndrome in aged humans [76]

bp(GO:autophagy) decreases a(CHEBI:lipid) View Subject | View Object

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Evidence 08cf149d03
JSON

While autophagic-lysosomal degradation is more commonly associated with protein degradation, it serves to degrade all cellular material including carbohydrates and lipids.

bp(GO:autophagy) increases deg(a(CHEBI:lipid)) View Subject | View Object

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bp(GO:autophagy) increases deg(a(CHEBI:carbohydrate)) View Subject | View Object

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Evidence 44ff6147f7
JSON

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87]

bp(GO:autophagy) increases deg(p(HGNC:MAPT)) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) increases bp(GO:autophagy) View Subject | View Object

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p(HGNC:PRKAA1) directlyIncreases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

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Evidence 98e78f42db
JSON

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38]

bp(GO:endocytosis) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(GO:endocytosis) association p(HGNC:BECN1) View Subject | View Object

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bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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bp(GO:macroautophagy) association p(HGNC:BECN1) View Subject | View Object

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p(HGNC:BECN1) association bp(GO:macroautophagy) View Subject | View Object

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p(HGNC:BECN1) association bp(GO:endocytosis) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

Appears in Networks:

Evidence b05a256a60
JSON

Since Nixon and colleagues first reported the pathological evidence of defective macroautophagy in EM images in the AD brain, similar observations have been made in cellular and animal models of AD [2,3,7,14]

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 0489d0d41f
JSON

Defects in macroautophagy in AD are supported by additional lines of evidence

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 8ad04ffac2
JSON

Maintenance of neuronal macroautophagy can counteract AD pathology [22,23].

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

Evidence 6ca753fe0c
JSON

Lastly, macroautophagy, but not UPS or CMA can clear protein aggregates.

bp(GO:macroautophagy) increases deg(a(HBP:"protein aggregates")) View Subject | View Object

Appears in Networks:

Evidence b3520f2ea8
JSON

Increased Aβ generation and accumulation in lysosomes suggest that Aβ metabolism, at least partially, is regulated by macroautophagy [3,14,32–34].

bp(GO:macroautophagy) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Lysosomes

Evidence 15c41453f9
JSON

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35].

bp(GO:macroautophagy) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

p(HGNC:BECN1) decreases a(MESH:"Amyloid beta-Peptides") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:BECN1) View Subject | View Object

Appears in Networks:

Evidence 736677bedb
JSON

Compromised macroautophagy, via the genetic suppression of Atg7, leads to the blockade of Aβ secretion and contributes to the subsequent diminution in extracellular Aβ plaque load

bp(GO:macroautophagy) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:

p(HGNC:ATG7) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 4bca3daff1
JSON

Wang et al., using an N2a neuroblastoma cell line that expresses the repeat domain of tau with an FTD-17 mutation (TauRDΔK280), has demonstrated that tau aggregates can be degraded by macroautophagy [48]

bp(GO:macroautophagy) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Appears in Networks:

Evidence 81a480441c
JSON

Finally, numerous studies using iPSC models have implicated changes in macroautophagy pathways in Parkinson’s disease [137–144], Gaucher disease [145], Niemann-Pick Type C1 disease [146–148] and diseases affecting motor neurons, including ALS [149,150], spinal and bulbar muscular atrophy (SBMA) [151], Brown- Vialetto disease [152], Charcot-Marie-Tooth 2A [153] and hereditary spastic paraplegia [154]

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Niemann-Pick Disease, Type C") View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Bulbo-Spinal Atrophy, X-Linked") View Subject | View Object

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Spastic Paraplegia, Hereditary") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

path(MESH:"Bulbo-Spinal Atrophy, X-Linked") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

path(MESH:"Niemann-Pick Disease, Type C") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

path(MESH:"Spastic Paraplegia, Hereditary") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 2220041162
JSON

However, recent work provides direct evidence that PICALM can also modulate macroautophagy, via its role in SNARE endocytosis to clear tau aggregates [102].

tloc(complex(GO:"SNARE complex"), fromLoc(GO:"extracellular space"), toLoc(GO:intracellular)) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Appears in Networks:

p(HGNC:PICALM) regulates bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:PICALM) increases tloc(complex(GO:"SNARE complex"), fromLoc(GO:"extracellular space"), toLoc(GO:intracellular)) View Subject | View Object

Appears in Networks:

Evidence 56c7c180c6
JSON

Aβ peptides originate from the transmembrane protein amyloid precursor protein (APP) which undergoes sequential cleavage via two distinct pathways by the enzyme complexes β- and γ-secretase [31]

complex(GO:"gamma-secretase complex") increases p(HGNC:APP, frag("?")) View Subject | View Object

Appears in Networks:

p(HGNC:APP) increases a(MESH:"Amyloid beta-Peptides") View Subject | View Object

Appears in Networks:

p(HGNC:BACE1) increases p(HGNC:APP, frag("?")) View Subject | View Object

Appears in Networks:

Evidence cb29ceb57e
JSON

Since the initial finding of proteasome-dependent degradation of α-synuclein [58], significant efforts have been made to clarify the modes of α-synuclein metabolism

complex(GO:"proteasome complex") increases deg(p(HGNC:SNCA)) View Subject | View Object

Appears in Networks:

Evidence 255a4a493a
JSON

Cytosolic tau is highest in density in membrane-rich axons and growth cones where lipid interaction with cytosolic tau may contribute to fibrillary tau aggregation [84].

complex(a(CHEBI:lipid), p(HGNC:MAPT)) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cytosol

Evidence 4fc1f2e66a
JSON

Tau serves an important function by enabling microtubules to connect with cytoskeletal components and facilitates anterograde and retrograde axonal transport of vesicles and organelles [39].

p(HGNC:MAPT) increases complex(a(GO:cytoskeleton), a(GO:microtubule)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) increases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) increases bp(GO:"retrograde axonal protein transport") View Subject | View Object

Appears in Networks:

Evidence 246e16ad56
JSON

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP).

p(HGNC:MAPT) association path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

p(HGNC:MAPT) association path(MESH:"Frontotemporal Dementia") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT) association path(MESH:"Niemann-Pick Diseases") View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

path(MESH:"Frontotemporal Dementia") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

path(MESH:"Niemann-Pick Diseases") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

path(MESH:Dementia) association path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:

path(MESH:Tauopathies) association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

path(MESH:Tauopathies) association path(MESH:Dementia) View Subject | View Object

Appears in Networks:

Evidence 0e617103f4
JSON

NBR1 colocalizes with tau and has primary sequence domains for binding [52].

p(HGNC:MAPT) association p(HGNC:NBR1) View Subject | View Object

Appears in Networks:

p(HGNC:NBR1) association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:

Evidence f3053f4c4f
JSON

In a more recent GWAS investigation, TREM2 (triggering receptor expressed on myeloid cells 2) was identified as one of the markers strongly associated with increased levels of tau and phosphorylated tau in cerebrospinal fluid from AD patients [91].

p(HGNC:MAPT) positiveCorrelation p(HGNC:TREM2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:TREM2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:TREM2) positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:TREM2) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

Evidence bc22979fae
JSON

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29].

p(HGNC:SNCA) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:SNCA) increases path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(MESH:"Amyloid beta-Peptides", pmod(HBP:misfolding)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SNCA) View Subject | View Object

Appears in Networks:

Evidence 43c2afe659
JSON

Recent clinical and immunohistochemistry studies demonstrate the contribution of α-synuclein in the development of AD pathology

p(HGNC:SNCA) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

Evidence bc4bdcf536
JSON

One intriguing molecule that interacts with VPS35 is SORL1, a VPS10P-domain receptor protein that has been linked to autosomal dominant early-onset AD [116,117].

p(HGNC:SORL1) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:VPS35) directlyIncreases complex(p(HGNC:SORL1), p(HGNC:VPS35)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:SORL1) View Subject | View Object

Appears in Networks:

Evidence 40fe7c5561
JSON

VPS35, one of the retromer-related genes identified from GWAS datasets on AD [110], regulates TREM2’s function in microglia [111].

p(HGNC:VPS35) regulates act(p(HGNC:TREM2)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 45b0dd1f13
JSON

Another modulator of A-LS implicated in AD pathology is transcription factor EB (TFEB), a master regulator of lysosome biogenesis

p(HGNC:TFEB) regulates bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:TFEB) regulates a(GO:lysosome) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence 608e6e9d1f
JSON

Activation of PTEN, another inducer of macroautophagy, by TFEB is indispensable for this TFEB-mediated increase in macroautophagy [89]

p(HGNC:TFEB) increases act(p(HGNC:PTEN)) View Subject | View Object

Appears in Networks:

composite(p(HGNC:PTEN), p(HGNC:TFEB)) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:PTEN) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

Evidence 2bdb8b5b16
JSON

However, in another study, iPSC-derived tau A152T and MAPT IVS 10+16 (a tau splice mutant) cortical neurons had increased cell death in response to rapamycin treatment, although basal cell death was ∼10 times higher in these tau mutants relative to controls, making interpretation of the work difficult [134].

composite(a(CHEBI:sirolimus), p(HGNC:MAPT, var("p.Ala152Thr"))) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:

Evidence 23b46da3f8
JSON

For example, in tau A152T iPSC-derived cortical neurons, total and phosphorylated Tau levels are elevated, particularly the insoluble forms [133], which is associated with decreases in UPS function as measured by total polyubiquitinated proteins and an upregulation of macroautophagy markers.

p(HGNC:MAPT, var("p.Ala152Thr")) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Ala152Thr")) decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Ala152Thr")) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation p(HGNC:MAPT, var("p.Ala152Thr")) View Subject | View Object

Appears in Networks:

Evidence 698ea32fd7
JSON

For instance, adenosine monophosphate- activated protein kinase (AMPK) phosphorylates ULK1 and inactivates mTOR through the raptor and tuberous sclerosis complex (TSC2).

composite(p(FPLX:AMPK), p(HGNC:TSC2)) decreases act(p(HGNC:MTOR)) View Subject | View Object

Appears in Networks:

p(FPLX:AMPK) increases p(HGNC:ULK1, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence d906360270
JSON

For instance, ApoE4–an important determinant of cholesterol metabolism and the strongest genetic risk factor for sporadic AD – regulates Aβ degradation [77].

g(HBP:"APOE e4") increases bp(GO:"cholesterol metabolic process") View Subject | View Object

Appears in Networks:

g(HBP:"APOE e4") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

g(HBP:"APOE e4") regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:

Evidence fde0704235
JSON

Tau phosphorylation, the major disease-related post-translational modification, is highly regulated by glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and other kinases.

p(FPLX:MAPK) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:CDK5) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

p(HGNC:GSK3B) increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:

Evidence 8c0b75a126
JSON

For example, Beclin 1 suppression results in impaired microglial phagocytosis of Aβ and reduced recycling of TREM2 [108].

p(HGNC:BECN1) increases bp(GO:phagocytosis) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence 3c5067804b
JSON

BIN1 is involved in the endocytosis and the endosomal sorting of membrane proteins

p(HGNC:BIN1) increases bp(GO:endocytosis) View Subject | View Object

Appears in Networks:

Evidence c423a41bb8
JSON

Similar to PICALM, BIN1, due to its role in endocytosis and trafficking, is implicated in APP metabolism [103].

p(HGNC:BIN1) increases bp(GO:"amyloid precursor protein metabolic process") View Subject | View Object

Appears in Networks:

Evidence 6b0a46f7e5
JSON

Suppression of BIN1 disrupts cellular trafficking of BACE1 and reduces BACE1 lysosomal degradation, leading to increased Aβ production [103].

p(HGNC:BIN1) increases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:BIN1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

Evidence 8e43decf4b
JSON

Higher expression of BIN1 has been reported in AD brains, and suppression of BIN1 reduces tau toxicity, suggesting BIN1 involvement in tau pathology, as well [104].

p(HGNC:BIN1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:BIN1) positiveCorrelation path(MESH:Tauopathies) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:BIN1) View Subject | View Object

Appears in Networks:

path(MESH:Tauopathies) positiveCorrelation p(HGNC:BIN1) View Subject | View Object

Appears in Networks:

Evidence d9d7a4e3b7
JSON

However, when tau becomes hyperphosphorylated, it detaches from microtubules and aggregates, resulting in depolymerization of microtubules and formation of insoluble tau deposits [40]

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases complex(a(GO:microtubule), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases bp(GO:"microtubule depolymerization") View Subject | View Object

Appears in Networks:

Evidence 5d5980896e
JSON

A recent line of work revealed Aβ-promoting function of PICALM by demonstrating that PICALM depletion decreased Aβ generation through disrupting clathrin-mediated endocytosis and internalization of γ-secretase [99,100].

p(HGNC:PICALM) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

p(HGNC:PICALM) increases bp(GO:"clathrin-dependent endocytosis") View Subject | View Object

Appears in Networks:

p(HGNC:PICALM) increases tloc(complex(GO:"gamma-secretase complex"), fromLoc(GO:"extracellular space"), toLoc(GO:intracellular)) View Subject | View Object

Appears in Networks:

Evidence 513507cda2
JSON

PICALM may also promote amyloid clearance from the brain by internalizing Aβ into endothelial cells and ultimately into to the bloodstream [101]

p(HGNC:PICALM) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:"Endothelial Cells"), toLoc(MESH:Blood)) View Subject | View Object

Appears in Networks:

Evidence b929d4af10
JSON

Multiple large-scale GWAS demonstrate that variants of PICALM (phosphatidylinositol-L-binding clathrin assembly protein involved in endocytosis) are significantly associated with AD [90,93,94].

p(HGNC:PICALM, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:PICALM, var("?")) View Subject | View Object

Appears in Networks:

Evidence 880d998a68
JSON

PSEN1 M146L and A246E mutant cortical neurons have been shown to possess decreased activation of the CLEAR (coordinated lysosomal expression and regulation) gene network, as measured by a TFEB-driven luciferase assay, consistent with a reduction in autophagic activity [131].

p(HGNC:PSEN1, var("p.Ala246Glu")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

p(HGNC:PSEN1, var("p.Met146Leu")) decreases bp(GO:autophagy) View Subject | View Object

Appears in Networks:

Evidence ef22658b57
JSON

In a similar vein, PSEN1 A246E mutant cortical neurons have reduced mitophagy compared to control neurons, which is associated more with decreased lysosomal function rather than mitochondrial targeting [132].

p(HGNC:PSEN1, var("p.Ala246Glu")) decreases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:

p(HGNC:PSEN1, var("p.Ala246Glu")) decreases act(a(GO:lysosome)) View Subject | View Object

Appears in Networks:

Evidence 164b572dca
JSON

Evidence that p62 facilitates tau degradation has been demonstrated in several studies where p62 colocalized with tau in NFTs from AD patients [53].

p(HGNC:SQSTM1) increases deg(p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:

Evidence 5b4c993051
JSON

For example, Babu et al. has shown that p62−/− knockout mice have increased levels of hyperphosphorylated tau, reduction of synaptophysin and changes in short term memory compared to p62+/− [54]

p(HGNC:SQSTM1) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

p(HGNC:SQSTM1) increases p(HGNC:SYP) View Subject | View Object

Appears in Networks:

p(HGNC:SQSTM1) regulates bp(GO:"short-term memory") View Subject | View Object

Appears in Networks:

Evidence aaeae1dac4
JSON

Another common proteinopathy occurs from the misfolding of TARDNA binding protein 43 kDa (TDP-43), which is primarily seen in amyotrophic lateral sclerosis (ALS) and FTD [67]

p(HGNC:TARDBP, pmod(HBP:misfolding)) positiveCorrelation path(MESH:"Amyotrophic Lateral Sclerosis") View Subject | View Object

Appears in Networks:

p(HGNC:TARDBP, pmod(HBP:misfolding)) positiveCorrelation path(MESH:"Frontotemporal Dementia") View Subject | View Object

Appears in Networks:

path(MESH:"Amyotrophic Lateral Sclerosis") positiveCorrelation p(HGNC:TARDBP, pmod(HBP:misfolding)) View Subject | View Object

Appears in Networks:

path(MESH:"Frontotemporal Dementia") positiveCorrelation p(HGNC:TARDBP, pmod(HBP:misfolding)) View Subject | View Object

Appears in Networks:

Evidence 1cdd6d7ac8
JSON

TFEB at normal state is phosphorylated by mTOR complex 1, which inhibits its activity

p(HGNC:TFEB, pmod(Ph)) decreases act(p(HGNC:TFEB)) View Subject | View Object

Appears in Networks:

Evidence 8de3177086
JSON

Recent work by Ulland et al. has also discovered an additional function of TREM2 in the maintenance of microglial macroautophagy and metabolism

p(HGNC:TREM2) increases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

p(HGNC:TREM2) increases bp(GO:"metabolic process") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell

Evidence f934797a01
JSON

TREM2 deficiency in an AD mouse model results in suppressed metabolic function in microglia through the dampening of the mTOR signaling pathway, which subsequently elicits a compensatory autophagic response to address the metabolic defect [109].

p(HGNC:TREM2) increases bp(GO:"metabolic process") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell
MeSH
Alzheimer Disease

p(HGNC:TREM2) increases act(complex(GO:"TOR complex")) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell
MeSH
Alzheimer Disease

Evidence edca721eaa
JSON

Variants of TREM2 have been found to increase the risk of developing AD by approximately three times [105,106], further validating it as a risk factor for AD.

p(HGNC:TREM2, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

Evidence 3bfa4f0992
JSON

VPS35 mutations have been shown to disrupt macroautophagy [113] and mitochondrial function [114] and are associated with AD and PD [102,115].

p(HGNC:VPS35, var("?")) decreases bp(GO:macroautophagy) View Subject | View Object

Appears in Networks:

p(HGNC:VPS35, var("?")) decreases act(a(GO:mitochondrion)) View Subject | View Object

Appears in Networks:

p(HGNC:VPS35, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:VPS35, var("?")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:VPS35, var("?")) View Subject | View Object

Appears in Networks:

path(MESH:"Parkinson Disease") association p(HGNC:VPS35, var("?")) View Subject | View Object

Appears in Networks:

Evidence c5a07a910d
JSON

Accumulation of misfolded proteins and damaged organelles is highly detrimental for neuronal homeostasis and survival.

p(MESH:Proteins, pmod(HBP:misfolding)) decreases bp(GO:"neuron cellular homeostasis") View Subject | View Object

Appears in Networks:

p(MESH:Proteins, pmod(HBP:misfolding)) decreases a(MESH:Neurons) View Subject | View Object

Appears in Networks:

Evidence e960bfb995
JSON

Altogether, as with proteinopathy, accumulation of damaged or dysfunctional mitochondria is detrimental to the development of AD pathologies

path(HBP:"mitochondrial dysfunction") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

Evidence be7c6efd5e
JSON

Dysfunctional mitochondria are critically harmful to cells, as this leads to decreased synthesis of cellular ATP and accumulation of ROS, which further overburden and damage other functional mitochondria.

path(HBP:"mitochondrial dysfunction") decreases a(CHEBI:ATP) View Subject | View Object

Appears in Networks:

path(HBP:"mitochondrial dysfunction") increases a(CHEBI:"reactive oxygen species") View Subject | View Object

Appears in Networks:

Evidence 04a57c4c04
JSON

Previous studies demonstrate impaired mitochondrial function preceding the accumulation of hallmark proteins in AD, such as Aβ [123,124] and tau [125].

path(HBP:"mitochondrial dysfunction") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(HBP:"mitochondrial dysfunction") increases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

Evidence bc56cc0546
JSON

Thus, as a quality control mechanism, mitophagy − a form of selective macroautophagy that specifically targets mitochondria − occurs in response to damaged or dysfunctional mitochondria in order to prevent mitochondrial bioenergetic deficits.

path(HBP:"mitochondrial dysfunction") increases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:

Evidence 3124399e7b
JSON

Recently, a comprehensive investigation utilizing gene expression analysis of the hippocampal region (CA1) of patients with Alzheimer’s disease identified that autophagosome formation and lysosomal biogenesis genes were upregulated at early stages of AD [21]

path(MESH:"Alzheimer Disease") increases a(GO:lysosome) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

path(MESH:"Alzheimer Disease") increases a(GO:autophagosome) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

Evidence 9537ae54b6
JSON

A recent study reported that mitophagy is robustly induced in AD brains and in vitro models of mutant APP, accompanied with abnormal accumulation of depoloarized mitochondria [126]

path(MESH:"Alzheimer Disease") increases bp(GO:mitophagy) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 820a682edb
JSON

Formation of amyloid β (Aβ) plaques is one of the most notable hallmarks in AD pathology [30]

path(MESH:"Parkinson Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:

Evidence 14a87746a2
JSON

Cytosolic lipids are stored as triglycerides in lipid droplets and are hydrolyzed into fatty acid for energy under nutrient starvation

path(MESH:Starvation) increases rxn(reactants(a(CHEBI:lipid)), products(a(CHEBI:"fatty acid"))) View Subject | View Object

Appears in Networks:

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.