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PubMed: 26195256

Title
Clearance systems in the brain-implications for Alzheimer disease.
Journal
Nature reviews. Neurology
Volume
11
Issue
None
Pages
457-70
Date
2015-08-01
Authors
Zetterberg H | Tarasoff-Conway JM | de Leon MJ | Axel L | Blennow K | Butler T | Carare RO | Fieremans E | Frangione B | Glodzik L | Ménard J | Nicholson C | Osorio RS | Rusinek H | Wisniewski T | Zlokovic BV

Evidence e43a5657a0
JSON

Given the size of AD-related proteins, mono- meric Aβ1-40, Aβ1-42 and tau, should be able to pass freely through astrocytic endfeet clefts at the glial barrier.72

a(CHEBI:"amyloid-beta polypeptide 40") association path(MESH:"Alzheimer Disease") View Subject | View Object

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a(CHEBI:"amyloid-beta polypeptide 42") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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Evidence 0e5b0da487
JSON

In addition, insulin-degrading enzyme has been proposed to have a role in Aβ clearance through the BBB, which might explain why BBB clearance is sensitive to insulin.144

a(CHEBI:"amyloid-beta") association a(MESH:Insulin) View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

a(MESH:Insulin) association a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 1597fe5b1b
JSON

Aβ is cleared along perivascular drainage pathways.83 In both AD44,160 and CAA44 (commonly associated with AD84), perivascular drainage of Aβ is impaired.

a(CHEBI:"amyloid-beta") association bp(HBP:"perivascular drainage pathways") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

bp(HBP:"perivascular drainage pathways") association a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence ba30a0e8c7
JSON

In the early 2000s, mouse studies demonstrated that the majority (75%) of extracellular Aβ (eAβ) is cleared by the BBB, with only a minority (10%) being cleared by ISF bulk flow.

a(MESH:"Blood-Brain Barrier") decreases p(CHEBI:"amyloid-beta", loc(GO:"extracellular region")) View Subject | View Object

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a(MESH:"Extracellular Fluid") decreases p(CHEBI:"amyloid-beta", loc(GO:"extracellular region")) View Subject | View Object

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Evidence cfb228fb4c
JSON

Third, ApoE4 is also associated with lower antioxidant activity than other ApoE isoforms,154,155 and it mediates BBB breakdown through a proinflammatory pathway involving cyclophilin A in pericytes.

act(a(MESH:"Blood-Brain Barrier")) association p(HGNC:PPIA) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HBP:"APOE e4") regulates a(MESH:"Blood-Brain Barrier") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:PPIA) association act(a(MESH:"Blood-Brain Barrier")) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence ee228244c5
JSON

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI.

a(MESH:"Cerebral Cortex") association path(MESH:"Alzheimer Disease") View Subject | View Object

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a(MESH:"Cerebral Ventricles") association path(MESH:"Alzheimer Disease") View Subject | View Object

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a(MESH:"Prefrontal Cortex") association path(MESH:"Alzheimer Disease") View Subject | View Object

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a(MESH:"White Matter") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Pick Disease of the Brain") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(MESH:"Prefrontal Cortex") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(MESH:"Cerebral Cortex") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(MESH:"Cerebral Ventricles") View Subject | View Object

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path(MESH:"Alzheimer Disease") association a(MESH:"White Matter") View Subject | View Object

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path(MESH:"Pick Disease of the Brain") association path(MESH:"Alzheimer Disease") View Subject | View Object

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Evidence a9b9893b8c
JSON

Specifically, ISF Aβ can be taken up by microglia and astrocytes, whereas perivascular Aβ can be degraded by vascular smooth muscle cells, perivascular macrophages, and astrocytes

a(MESH:"Muscle, Smooth, Vascular") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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a(MESH:Astrocytes) decreases a(CHEBI:"amyloid-beta", loc(MESH:"Extracellular Fluid")) View Subject | View Object

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a(MESH:Microglia) decreases a(CHEBI:"amyloid-beta", loc(MESH:"Extracellular Fluid")) View Subject | View Object

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Evidence 4ae4a4fd32
JSON

Extracellular degradation of ISF proteins mainly consists of degradation by proteases expressed and secreted by cells such as astrocytes

act(a(MESH:Astrocytes)) decreases p(HGNC:APP) View Subject | View Object

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Evidence f65463de96
JSON

Second, both Aβ and insulin are ligands that compete for degradation by insulin-degrading enzyme; thus, hyper- insulinaemia can reduce clearance of Aβ, which might partly explain the link between type 2 diabetes mellitus and AD.

a(MESH:Insulin) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence deda2a00bc
JSON

Soluble Aβ can be removed from the brain by various clearance systems, including enzymatic degradation and cellular uptake, transport across the blood–brain barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB), interstitial fluid (ISF) bulk flow, and cerebro- spinal fluid (CSF) absorption into the circulatory and lymphatic systems.

bp(GO:"import into cell") decreases a(HBP:"amyloid-beta derived diffusible ligands") View Subject | View Object

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Evidence 225b0d1188
JSON

Intracellular degradation of proteins occurs via the ubiquitin– proteasome pathway, the autophagy–lysosome pathway, and the endosome–lysosome pathway.56

act(complex(a(MESH:Endosomes), a(MESH:Lysosomes))) decreases p(HGNC:APP) View Subject | View Object

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

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act(p(MESH:Ubiquitin)) decreases p(HGNC:APP) View Subject | View Object

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Evidence 4f40d1e2d9
JSON

These findings are in line with evidence suggesting that increased oxi- dative stress157 and loss of vascular integrity contribute to ageing158 and AD,159 as demonstrated by accelerated breakdown of the BBB and the neurovascular unit.

bp(MESH:"Oxidative Stress") increases path(MESH:Aging) View Subject | View Object

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Hippocampus
MeSH
Temporal Lobe

Evidence 9d52fecfad
JSON

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes.

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

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

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g(HGNC:PSEN2, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

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

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path(MESH:"Alzheimer Disease") association g(HGNC:PSEN2, var("?")) View Subject | View Object

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

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Evidence 385d67fa9e
JSON

ecifically, Aβ accumulation into extracellular plaques is marked by decreased CSF levels of Aβ1–42, and tau accumulation into NFTs is marked by increased CSF levels of total tau and hyperphosphory- lated tau.

p(CHEBI:"amyloid-beta polypeptide 42", loc(MESH:"Cerebrospinal Fluid")) negativeCorrelation p(HGNC:APP, loc(GO:"extracellular region")) View Subject | View Object

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p(HGNC:APP, loc(GO:"extracellular region")) negativeCorrelation p(CHEBI:"amyloid-beta polypeptide 42", loc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

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p(HGNC:MAPT, loc(MESH:"Neurofibrillary Tangles")) positiveCorrelation p(HGNC:MAPT, loc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

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p(HGNC:MAPT, loc(MESH:"Cerebrospinal Fluid")) positiveCorrelation p(HGNC:MAPT, loc(MESH:"Neurofibrillary Tangles")) View Subject | View Object

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Evidence 3dc5563247
JSON

The strongest identified genetic risk factor for LOAD is the apolipoprotein E (APOE) ε4 allele (APOE*ε4),

p(HBP:"APOE e4") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HBP:"APOE e4") View Subject | View Object

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Evidence 9281b0e27c
JSON

The pres- ence of ApoE4 is associated with reduced perivascular drainage of Aβ,161 which in turn is linked to deposition of immune complexes.

p(HBP:"APOE e4") decreases bp(HBP:"perivascular drainage pathways") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 724875a847
JSON

These findings support the link between TBI and tau aggre- gation, with resulting neurodegeneration similar to that seen in AD and chronic traumatic encephalopathy

p(HBP:"tau aggregates") association path(MESH:"Brain Injuries, Traumatic") View Subject | View Object

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MeSH
Choroid Plexus

path(MESH:"Brain Injuries, Traumatic") association p(HBP:"tau aggregates") View Subject | View Object

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MeSH
Choroid Plexus

Evidence 94c200bd20
JSON

Clearance of Aβ through the BBB is also medi- ated by α2-macroglobulin (α2M),14 and LDLR-related protein 2 (LRP2, also known as megalin) when LRP2 forms a complex with clusterin (also known as ApoJ).

p(HGNC:A2M) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

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Hippocampus
MeSH
Temporal Lobe

p(HGNC:LRP2) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence eaccc4c249
JSON

The main ABC transporter responsible for Aβ efflux is ABCB1 (also known as P-glycoprotein 1 or MDR1),which directly exports Aβ into the circulation.

p(HGNC:ABCB1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 1d98d52e33
JSON

The main ABC transporter responsible for Aβ efflux is ABCB1 (also known as P-glycoprotein 1 or MDR1), which directly exports Aβ into the circulation.

p(HGNC:ABCB1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 84961d0858
JSON

In AD, these factors are impaired in a number of ways. First, expression of the blood efflux transporters LRP1123 and ABCB1147 is decreased, whereas expression of the blood influx transporter RAGE is upregulated.

path(MESH:"Alzheimer Disease") decreases p(HGNC:LRP1) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") decreases p(HGNC:ABCB1) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

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

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 235d35b3a7
JSON

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme.

p(HGNC:ACE) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(HGNC:IDE) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:"Endothelin-Converting Enzymes") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:"Glutamate Carboxypeptidase II") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:"Matrix Metalloproteinase 2") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:"Matrix Metalloproteinase 3") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:"Matrix Metalloproteinase 9") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:"Tissue Plasminogen Activator") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:Fibrinolysin) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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p(MESH:Neprilysin) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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Evidence cb36ed5e5d
JSON

Free Aβ can be transported from the circulation into the interstitium via RAGE (advanced glycosylation end product-specific receptor).

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

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence e4f12e8c71
JSON

which is located on the abluminal side of the brain endo- thelium,140 does not directly bind and extrude Aβ,141 but mediates Aβ clearance in an ApoE-dependent manner.

p(HGNC:APOE) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

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Hippocampus
MeSH
Temporal Lobe

Evidence 0a6607f83b
JSON

ApoE is a cholesterol transporter that competes with Aβ for efflux by LRP1 from the interstitium into the circula- tion;

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

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence e6093816f1
JSON

competition for shared receptors is the primary mechanism by which ApoE mediates Aβ clearance

p(HGNC:APOE) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence e5856c8a48
JSON

However, two-photon imaging studies from the past few years have suggested that ISF bulk flow—facilitated by astroglial aquaporin-4 (AQP4) channels and named the glymphatic (glial + lymphatic) system—contributes to a larger portion of eAβ clearance than previously thought.

act(p(HGNC:AQP4)) decreases p(CHEBI:"amyloid-beta", loc(GO:"extracellular region")) View Subject | View Object

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Evidence 82b15b1856
JSON

If APP is first cleaved by β-secretase 1 (also known as BACE1) instead of α-secretase, the subsequent γ-secretase cleavage will result in soluble monomeric Aβ.

act(p(HGNC:BACE1)) increases a(HBP:"amyloid-beta derived diffusible ligands") View Subject | View Object

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Evidence 87ad7eed5d
JSON

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29

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

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

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p(HGNC:TREM2) association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") association p(HGNC:TREM2) View Subject | View Object

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

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

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Evidence be93284492
JSON

Some evidence suggests that LRP1 is the main transporter for Aβ efflux at the BBB, whereas other studies have demonstrated its role to be quite minor.

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 6284deef94
JSON

Specifically, local soluble Aβ is transferred from the interstitium to the brain by LDL receptor (LDLR) family members such as LRP1, and ATP-binding cassette transporters (ABC transporters).

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:"Nephritis, Interstitial"), toLoc(MESH:Brain)) View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 74cb6ae08b
JSON

Phosphorylation of tau by protein kinase A increases its resistance to degradation by calpain

p(HGNC:MAPT, pmod(Ph)) decreases act(p(MESH:Calpain)) View Subject | View Object

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MeSH
Choroid Plexus

p(MESH:"Cyclic AMP-Dependent Protein Kinases") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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MeSH
Choroid Plexus

act(p(MESH:Calpain)) decreases p(HGNC:MAPT) View Subject | View Object

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MeSH
Choroid Plexus

Evidence 88c2585f42
JSON

APP is cleaved by α-secretase, which precludes forma- tion of Aβ, and the resulting carboxy-terminal fragment is then cleaved by γ-secretase.103 The resulting products do not aggregate.104

act(p(MESH:"Amyloid Precursor Protein Secretases")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Evidence 3a39d3a6ab
JSON

Intracellular Aβ (iAβ) can be degraded by proteasomes via the ubiquitin–proteasome pathway in neurons,116 lyso- somal cathepsin enzymes,117 proteases (such as insulin- degrading enzyme, a thiol metalloendopeptidase that degrades monomeric Aβ) and insulin.

act(p(MESH:Cathepsins)) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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act(p(MESH:Ubiquitin)) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

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Evidence eb1fdd77e9
JSON

Tau is mainly cleared through intracellular degrada- tion by lysosomes via the autophagy–lysosome pathway, and by proteasomes via the ubiquitin–proteasome pathway.202

act(p(MESH:Lysosomes)) decreases p(HGNC:MAPT) View Subject | View Object

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MeSH
Choroid Plexus

p(MESH:Ubiquitin) decreases p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Choroid Plexus

Evidence 910a9388a0
JSON

Recent mouse studies suggest that the AQP4-dependent glymphatic pathway is an important clearance system for driving the removal of soluble Aβ from the interstitium.

act(p(MGI:Aqp4)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence dd11214097
JSON

Of note, a high-fat prenatal maternal diet has recently been reported to result in a failure of Aβ clearance along cerebrovascular basement membranes.

path(HBP:"high-fat prenatal maternal diet") increases a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 682019d1f4
JSON

Emerging evidence suggests that Aβ clearance is impaired in both early-onset and late-onset forms of AD.

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

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Evidence e40678b95e
JSON

Various factors have been reported to positively and negatively modulate the risk of LOAD. Specifically, the greatest overall risk factor for LOAD is ageing;

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

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

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Evidence ff7847406c
JSON

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD

path(MESH:"Alzheimer Disease") association path(MESH:"Cardiovascular Diseases") View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Diabetes Mellitus") View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:Hypertension) View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Craniocerebral Trauma") View Subject | View Object

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path(MESH:"Alzheimer Disease") association path(MESH:"Sleep Initiation and Maintenance Disorders") View Subject | View Object

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path(MESH:"Cardiovascular Diseases") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Craniocerebral Trauma") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Diabetes Mellitus") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Sleep Initiation and Maintenance Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:Hypertension) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

Evidence 6bd0aa8d6e
JSON

Recent advances now enable several AD-related brain changes to be detected in vivo: 18F-FDG-PET detects decreases in glucose metabolism,45,46 and MRI detects brain atrophy, as well as diffusion and perfu- sion abnormalities, which are most prominent in the vul- nerable hippocampal formation and cortical regions.

path(MESH:"Alzheimer Disease") decreases bp(GO:"glucose metabolic process") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases a(MESH:Brain) View Subject | View Object

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Evidence fbee260d84
JSON

First, expression of neprilysin is decreased in AD,126 especially in regions with high Aβ loads such as the hippocampus and temporal gyrus.127

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

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MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 0a3286d0b6
JSON

Although overall matrix metallo- proteinase 2 expression is increased in AD,58 its activity is reduced in astrocytes that surround Aβ plaques.

path(MESH:"Alzheimer Disease") increases p(HGNC:MMP2) View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 7d3da532b3
JSON

In AD, the choroid plexus undergoes many structural changes, such as calcification, fibrosis and Aβ deposition, all of which can obstruct CSF production.

path(MESH:"Alzheimer Disease") increases path(MESH:"Calcification, Physiologic") View Subject | View Object

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Annotations
MeSH
Choroid Plexus

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

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MeSH
Choroid Plexus

Evidence f2aa4b489c
JSON

These findings might partly explain why sleep impairment increases the risk of AD

path(MESH:"Sleep Initiation and Maintenance Disorders") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence d9ea6af1b9
JSON

First, in ageing, and particularly in AD, CSF production by the choroid plexus is reduced, as shown by decreased water secretion into the ventricles via AQP1 water channels.

path(MESH:Aging) decreases a(MESH:"Cerebrospinal Fluid") View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 18c3e9a5a6
JSON

Inflammation, a common feature of AD, can affect ligand affinity by making the pH more acidic, which promotes hyperphosphorylation of tau and induces conforma- tional changes in Aβ that hinder its clearance.

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

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

Evidence 85bfec3645
JSON

Thus, sleep could indirectly increase BBB clearance of Aβ through increased glymphatic bulk flow, but it might also directly increase clearance through the BBB via various mechanisms, such as molecular changes (for example, upregulated LRP1), as seen with AD-protective physical and cognitive activity in mice.1

path(MESH:Sleep) increases act(a(MESH:"Blood-Brain Barrier")) View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:Sleep) increases bp(HBP:"glymphatic bulk flow") View Subject | View Object

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

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.