Faculty Opinions recommendation of Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization.

The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized Aβ more efficiently than astrocytes and HSC degraded Aβ leading to suppressed expression of α-smooth muscle actin (α-SMA), collagen 1 and transforming growth factor β (TGFβ). Aβ also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGFβ in cultured human liver sinusoidal endothelial cells (hLSEC). Liver Aβ levels also correlate with the expression of eNOS in transgenic Alzheimer’s disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of Aβ in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation.

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Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis

Clinical Epigenetics ◽

10.1186/s13148-020-00967-6 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Antonella De Lillo ◽

Gita A. Pathak ◽

Flavio De Angelis ◽

Marco Di Girolamo ◽

Marco Luigetti ◽

...

Keyword(s):

Amyloid Beta ◽

Molecular Mechanisms ◽

Regression Coefficient ◽

Phenotypic Variability ◽

Interaction Network ◽

Fiber Formation ◽

Transthyretin Amyloidosis ◽

Beta Secretase ◽

Life Threatening ◽

Amyloid Fiber Formation

AbstractHereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = −0.60, p = 6.26 × 10–8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer’s disease (KEGG hsa05010, q = 2.2 × 10–4). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = −2.18, p = 3.34 × 10–11). Cg13139646 showed co-methylation with cg19203115 (Pearson’s r2 = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = −0.56, p = 8.6 × 10–4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

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P3-352: Beta-secretase modulation and amyloid-beta production in rat brain primary cultures

Alzheimer s & Dementia ◽

10.1016/j.jalz.2008.05.1922 ◽

2008 ◽

Vol 4 ◽

pp. T625-T625

Author(s):

Daniele Zacchetti ◽

Barbara Bettegazzi ◽

Alessandra Consonni ◽

Romina Macco ◽

Ilaria Pelizzoni ◽

...

Keyword(s):

Rat Brain ◽

Amyloid Beta ◽

Primary Cultures ◽

Beta Secretase

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BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.160115697 ◽

2000 ◽

Vol 97 (17) ◽

pp. 9712-9717 ◽

Cited By ~ 250

Author(s):

M. Farzan ◽

C. E. Schnitzler ◽

N. Vasilieva ◽

D. Leung ◽

H. Choe

Keyword(s):

Amyloid Beta ◽

Precursor Protein ◽

Amyloid Beta Precursor Protein ◽

Beta Secretase

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Faculty Opinions recommendation of Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002150.11006 ◽

2001 ◽

Author(s):

David Matthews

Keyword(s):

Human Brain ◽

Beta Secretase ◽

Memapsin 2

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Human aspartic protease memapsin 2 cleaves the beta -secretase site of beta -amyloid precursor protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.97.4.1456 ◽

2000 ◽

Vol 97 (4) ◽

pp. 1456-1460 ◽

Cited By ~ 533

Author(s):

X. Lin ◽

G. Koelsch ◽

S. Wu ◽

D. Downs ◽

A. Dashti ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Beta Amyloid ◽

Aspartic Protease ◽

Precursor Protein ◽

Beta Secretase ◽

Memapsin 2

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Epigenetic profiling of Italian patients identified methylation sites associated with hereditary Transthyretin amyloidosis

10.1101/2020.04.13.20064006 ◽

2020 ◽

Author(s):

Antonella De Lillo ◽

Gita Pathak ◽

Flavio De Angelis ◽

Marco Di Girolamo ◽

Marco Luigetti ◽

...

Keyword(s):

Amyloid Beta ◽

Molecular Mechanisms ◽

Phenotypic Variability ◽

Interaction Network ◽

Fiber Formation ◽

Transthyretin Amyloidosis ◽

Beta Secretase ◽

Life Threatening ◽

Amyloid Fiber Formation

Hereditary Transthyretin (TTR) Amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers, We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (beta =-0.60, p=6.26x10-8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology:0050435, q=0.007), amyloid fiber formation (Reactome HSA-977225, q=0.008), and Alzheimers disease (KEGG hsa05010, q=2.2x10-4). Additionally, TTR and BACE2 share APP (Amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (beta=-2.18, p=3.34x10-11). Cg13139646 showed co-methylation with cg19203115 (r2=0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (beta=-0.56, p=8.6x10-4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

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