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PubMed: 23528736

Title
Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system.
Journal
Progress in neurobiology
Volume
105
Issue
None
Pages
49-59
Date
2013-06-01
Authors
Lee JH | Lee MJ | Rubinsztein DC

Evidence 705108a6f4
JSON

UBB+ 1-capped polyUb chains are resistant to deubiquitination and inhibit proteasomal activity, which may mediate neurodegeneration through mitochondrial stress and p53 activation in neurites (Tan et al., 2007).

p(HBP:"UBB+1") decreases bp(GO:"protein deubiquitination") View Subject | View Object

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p(HBP:"UBB+1") decreases act(p(FPLX:Proteasome)) View Subject | View Object

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p(HBP:"UBB+1") increases bp(HP:Neurodegeneration) View Subject | View Object

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p(HBP:"UBB+1") increases bp(MESH:"Stress, Physiological") View Subject | View Object

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Annotations
MeSH
Mitochondria
MeSH
Neurites

p(HBP:"UBB+1") increases act(p(HGNC:TP53)) View Subject | View Object

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Annotations
MeSH
Neurites

Evidence 1dec62e7ce
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Trehalose, an natural disaccharide and mTOR-independent activator of autophagy (Sarkar et al., 2007), showed an effect on neuronal survival, reducing the level of tau aggregates in the brain of human tauopathy model mice (Kruger et al., 2011; Rodriguez-Navarro et al., 2010; Schaeffer et al., 2012).

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

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a(CHEBI:"alpha,alpha-trehalose") decreases bp(GO:"neuron apoptotic process") View Subject | View Object

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a(CHEBI:"alpha,alpha-trehalose") decreases a(HBP:"Tau aggregates") View Subject | View Object

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Annotations
MeSH
Brain

Evidence ff85a2f95a
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and lithium (Shimada et al., 2012) in human tau over-expressing Tg mice induced autophagy, which is accompanied by the reduced levels of pathological tau and NFT formation in tauopathy model mice.

a(CHEBI:"lithium atom") decreases a(HP:"Neurofibrillary tangles") View Subject | View Object

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Annotations
MeSH
Tauopathies

a(CHEBI:"lithium atom") increases bp(GO:autophagy) View Subject | View Object

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a(CHEBI:"lithium atom") decreases p(HGNC:MAPT) View Subject | View Object

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Annotations
MeSH
Tauopathies

Evidence b0c44b4279
JSON

Methylene blue, which has been known to directly inhibit tau aggregation, is also capable to induce autophagy and reduce total and phospho-tau levels with improved cognitive performance in tau transgenic mice by oral administration (Congdon et al., 2012).

a(CHEBI:"methylene blue") decreases a(HBP:"Tau aggregates") View Subject | View Object

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a(CHEBI:"methylene blue") increases bp(GO:autophagy) 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:MAPT, pmod(Ph)) View Subject | View Object

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Evidence a5f438a94f
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Related to these data, reversible and irreversible proteasome inhibitors including lactacystin, leupeptin, and epoxomicin delay the degradation of endogenous and/or transiently overexpressed tau (Cardozo and Michaud, 2002; David et al., 2002; Zhang et al., 2005).

a(CHEBI:epoxomicin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

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

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a(CHEBI:lactacystin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

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

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a(CHEBI:leupeptin) decreases act(p(FPLX:Proteasome)) View Subject | View Object

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

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Evidence d41288fcc7
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Autophagy inducers, including rapamycin (Fig. 3A), facilitate the degradation of insoluble forms of tau and also protect against its toxicity in Drosophila (Berger et al., 2006).

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

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Evidence 4e370a7ef7
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Recent evidence has shown that dysfunction in the UPS is closely related with tau degradation/aggregation and neurodedeneration in AD.

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

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Annotations
MeSH
Alzheimer Disease

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

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Annotations
MeSH
Alzheimer Disease

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

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Annotations
MeSH
Alzheimer Disease

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

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Annotations
MeSH
Alzheimer Disease

Evidence abaae69621
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Blocking proteasomes using Ab oligomers also effectively facilitates tau accumulation in AD mice (Tseng et al., 2008).

a(HBP:"amyloid-beta oligomers") decreases act(p(FPLX:Proteasome)) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT) View Subject | View Object

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Annotations
MeSH
Alzheimer Disease

Evidence dff61d4399
JSON

PHF-tau isolated from human AD brains in the soluble state was not degraded by the proteasome but instead functioned as an inhibitor of its activity (Keck et al., 2003).

a(HP:"Neurofibrillary tangles") decreases act(p(FPLX:Proteasome)) View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence d5a0496124
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A Ub with a 19-residue C-terminal extension from the UBB gene, or UBB+1 (Fig.2A) is selectively expressed in the brains of AD patients (van Leeuwen et al.,1998) and is often found to be accumulated in NFT in Alzheimer’s disease and other tauopathies

a(MESH:"Neurofibrillary Tangles") association p(HBP:"UBB+1") View Subject | View Object

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MeSH
Brain
MeSH
Alzheimer Disease

p(HBP:"UBB+1") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

p(HBP:"UBB+1") association a(MESH:"Neurofibrillary Tangles") View Subject | View Object

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"UBB+1") View Subject | View Object

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Annotations
MeSH
Brain

Evidence 25cf0f73ac
JSON

For example, the small molecule IU1 was recently identified from a high-throughput screen as a potent and selective inhibitor of USP14,

a(PUBCHEM:675434) decreases act(p(HGNC:USP14)) View Subject | View Object

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Evidence 19a3b84608
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In a cell-based assay, IU1 treatment increased proteasomal activity to result in accelerated degradation rates of tau and oxidatively damaged proteins.

a(PUBCHEM:675434) increases deg(p(HGNC:MAPT)) View Subject | View Object

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a(PUBCHEM:675434) increases act(p(FPLX:Proteasome)) View Subject | View Object

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Evidence 6a5cf95b7e
JSON

Oxidative stress also upregulates autophagy induction, which limits the production of reactive oxygen species from dysfunctional mitochondria.

bp(GO:"response to oxidative stress") increases bp(GO:autophagy) View Subject | View Object

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Evidence 3524945be7
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Tau proteins in a variety of forms are reported as degraded through the autophagy-lysosome system.

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

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Evidence 8fa66873f3
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Aging, a major risk factor for AD, affects both the UPS and autophagy.

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

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bp(MESH:Aging) decreases bp(GO:autophagy) View Subject | View Object

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bp(MESH:Aging) decreases act(p(FPLX:Proteasome)) View Subject | View Object

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Evidence c13de882d5
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Several E3 Ub ligases, such as CHIP, Parkin, RNF182, may have roles in AD and other neurodegenerative diseases (Shimura et al., 2004; Khandelwal et al., 2011; Lei et al., 2012).

p(HGNC:STUB1) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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p(HGNC:PRKN) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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p(HGNC:RNF182) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association p(HGNC:STUB1) View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association p(HGNC:PRKN) View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association p(HGNC:RNF182) View Subject | View Object

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Evidence 5ff6809e5c
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Further evidence of UPS-mediated tau degradation came from the identification of the tau E3 ligase, which is the carboxyl terminus of the Hsc70–interacting protein (CHIP)–Hsc70 complex, with UbcH5B as the E2 enzyme (Petrucelli et al., 2004; Shimura et al., 2004).

composite(p(HGNC:HSPA8), p(HGNC:STUB1), p(HGNC:UBE2D2)) increases deg(p(HGNC:MAPT)) View Subject | View Object

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Evidence 338ca0d70b
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The mammalian target of rapamycin (mTOR) kinase negatively modulates autophagy by phosphorylating Atg1, an autophagy initiating factor, while adenosine monophosphate-activated protein kinase (AMPK), a major sensor for the cellular energy status, activates autophagy through inhibiting mTOR signaling as well as by direct phosphorylation of Atg1 (Egan et al., 2011; Kim et al., 2011). Increased mTOR activity results in autophagy downregulation and tau accumulation.

p(FPLX:AMPK) increases bp(GO:autophagy) View Subject | View Object

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p(FPLX:AMPK) decreases act(p(FPLX:mTORC1)) View Subject | View Object

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

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p(FPLX:mTORC1) decreases bp(GO:autophagy) View Subject | View Object

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act(p(FPLX:mTORC1), ma(kin)) increases p(HGNC:ULK1, pmod(Ph)) View Subject | View Object

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act(p(FPLX:mTORC1)) increases p(HGNC:MAPT) View Subject | View Object

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p(HGNC:ULK1) increases bp(GO:autophagy) View Subject | View Object

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Evidence 808a350143
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Another DUB known to be mutated in familial neurodegenerative diseases is Ataxin-3 in the polyglutamine (polyQ) spinocerebellar ataxia type 3 (Kawaguchi et al., 1994).

p(HGNC:ATXN3, var("?")) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association p(HGNC:ATXN3, var("?")) View Subject | View Object

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Evidence 511db526b0
JSON

For instance, c-Jun NH 2-terminal kinase 1 (JNK1) may induce autophagy by phosphorylating Bcl-2 or Bim and abolishing their inhibitory effects on autophagy (Luo et al., 2012; Wei et al., 2008).

p(HGNC:BCL2) decreases bp(GO:autophagy) View Subject | View Object

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p(HGNC:BCL2L11) decreases bp(GO:autophagy) View Subject | View Object

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p(HGNC:MAPK8) increases bp(GO:autophagy) View Subject | View Object

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p(HGNC:MAPK8) increases p(HGNC:BCL2, pmod(Ph)) View Subject | View Object

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p(HGNC:MAPK8) increases p(HGNC:BCL2L11, pmod(Ph)) View Subject | View Object

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Evidence 9c87203d59
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Cathepsin D, a lysosomal protease, exhibited the capacity to degrade tau proteins in cultured hippocampal slices (Bednarski and Lynch, 1996).

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

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Evidence 1cb19ece98
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Moreover, constitutive inactivation of p62 in mice resulted in aggregated tau proteins with Lys63–Ub chains (Babu et al., 2008).

p(HGNC:DCTN4) decreases a(HBP:"Tau aggregates") View Subject | View Object

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Evidence 302fadf696
JSON

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ).

p(HGNC:RPS27A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:UBA52) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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

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

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

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

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:UBA52) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RPS27A) View Subject | View Object

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Evidence bf0cf98891
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Mutations in ubiquitin C-terminal hydrolase L1 (UCH-L1) have been proposed to have a role in various neurodegenerative diseases including AD, although the causality of mutations in this gene in Parkinson’s disease is now considered doubtful (Healy et al., 2006; Hutter et al., 2008).

p(HGNC:UCHL1, var("?")) association path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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p(HGNC:UCHL1, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HGNC:UCHL1, var("?")) View Subject | View Object

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path(MESH:"Neurodegenerative Diseases") association p(HGNC:UCHL1, var("?")) View Subject | View Object

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Evidence 70c8a76b32
JSON

Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B).

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNCGENEFAMILY:"Ubiquitin conjugating enzymes E2") View Subject | View Object

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p(HGNCGENEFAMILY:"Ubiquitin conjugating enzymes E2") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNCGENEFAMILY:"Ubiquitin like modifier activating enzymes") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNCGENEFAMILY:"Ubiquitin like modifier activating enzymes") View Subject | View Object

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Evidence 4c6b299c9e
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All three proteolytic activities have been reported to be decreased in AD brains (Keller et al., 2000).

path(MESH:"Alzheimer Disease") decreases bp(MESH:Proteolysis) View Subject | View Object

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Annotations
MeSH
Brain

Evidence 120afff72c
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Pathologically, the AD brains show both accumulated autophagosomes and autolysosomes, suggesting the basal autophagy process in neurons is abnormal in AD (Fig. 3A).

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

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MeSH
Brain

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

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MeSH
Brain

Evidence e0f7ba6b6b
JSON

The accumulated autophagic vacuoles in AD mainly reflect defected lysosomal clearance instead of induced autophagy.

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

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