| Reference | 1. J Immunol. 2017 Jul 1;199(1):224-232. doi: 10.4049/jimmunol.1601041. Epub 2017
May 22.
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The Role of Shed PrPc in the Neuropathogenesis of HIV Infection.
<br>
Megra BW(1), Eugenin EA(2)(3), Berman JW(4)(5)(6).
<br>
Author information: <br>
(1)Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.
(2)Public Health Research Institute, Newark, NJ 07103.
(3)Department of Microbiology and Molecular Genetics, Rutgers New Jersey Medical
School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
(4)Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
[email protected].
(5)Department of Microbiology, Albert Einstein College of Medicine, Bronx, NY
10461; and.
(6)Department of Immunology, Albert Einstein College of Medicine, Bronx, NY
10461.
<br>
HIV-1 enters the CNS soon after peripheral infection and causes chronic
neuroinflammation and neuronal damage that leads to cognitive impairment in
40-70% of HIV-infected people. The nonpathogenic cellular isoform of the human
prion protein (PrPc) is an adhesion molecule constitutively expressed in the CNS.
Previously, our laboratory showed that shed PrPc (sPrPc) is increased in the
cerebrospinal fluid of HIV-infected people with cognitive deficits as compared
with infected people with no impairment. In this article, we demonstrate that
CCL2 and TNF-α, inflammatory mediators that are elevated in the CNS of
HIV-infected people, increase shedding of PrPc from human astrocytes by
increasing the active form of the metalloprotease ADAM10. We show that the
consequence of this shedding can be the production of inflammatory mediators,
because treatment of astrocytes with rPrPc increased secretion of CCL2, CXCL-12,
and IL-8. Supernatants from rPrPc-treated astrocytes containing factors produced
in response to this treatment, but not rPrPc by itself, cause increased
chemotaxis of both uninfected and HIV-infected human monocytes, suggesting a role
for sPrPc in monocyte recruitment into the brain. Furthermore, we examined
whether PrPc participates in glutamate uptake and found that rPrPc decreased
uptake of this metabolite in astrocytes, which could lead to neurotoxicity and
neuronal loss. Collectively, our data characterize mediators involved in PrPc
shedding and the effect of this sPrPc on monocyte chemotaxis and glutamate uptake
from astrocytes. We propose that shedding of PrPc could be a potential target for
therapeutics to limit the cognitive impairment characteristic of neuroAIDS.
<br>
2. Fluids Barriers CNS. 2016 Aug 8;13(1):14. doi: 10.1186/s12987-016-0038-x.
<br>
Inhibition of ADAM10 promotes the clearance of Aβ across the BBB by reducing LRP1
ectodomain shedding.
<br>
Shackleton B(1)(2), Crawford F(3)(4), Bachmeier C(3)(4).
<br>
Author information: <br>
(1)The Roskamp Institute, Sarasota, FL, 34243, USA.
[email protected].
(2)The Open University, Milton Keynes, Buckinghamshire, MK7 6AA, UK.
[email protected].
(3)The Roskamp Institute, Sarasota, FL, 34243, USA.
(4)The Open University, Milton Keynes, Buckinghamshire, MK7 6AA, UK.
<br>
BACKGROUND: Transport across the blood-brain barrier (BBB) is an important
mediator of beta-amyloid (Aβ) accumulation in the brain and a contributing factor
in the pathogenesis of Alzheimer/’s disease (AD). One of the receptors responsible
for the transport of Aβ in the BBB is the low density lipoprotein
receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at
the cell surface, which prevents endocytic transport of ligands. Previously, we
reported a strong inverse correlation between LRP1 shedding in the brain and Aβ
transit across the BBB. Several proteases contribute to the ectodomain shedding
of LRP1 including the α-secretase, a desintegrin and metalloproteinase domain
containing protein 10 (ADAM10).<br>
METHODS: The role of ADAM10 in the shedding of LRP1 and Aβ BBB clearance was
assessed through pharmacological inhibition of ADAM10 in an in vitro model of the
BBB and through the use of ADAM10 endothelial specific knock-out mice. In
addition, an acute treatment paradigm with an ADAM10 inhibitor was also tested in
an AD mouse model to assess the effect of ADAM10 inhibition on LRP1 shedding and
Aβbrain accumulation.<br>
RESULTS: In the current studies, inhibition of ADAM10 reduced LRP1 shedding in
brain endothelial cultures and increased Aβ42 transit across an in vitro model of
the BBB. Similarly, transgenic ADAM10 endothelial knockout mice displayed lower
LRP1 shedding in the brain and significantly enhanced Aβ clearance across the BBB
compared to wild-type animals. Acute treatment with the ADAM10-selective
inhibitor GI254023X in an AD mouse model substantially reduced brain LRP1
shedding and increased Aβ40 levels in the plasma, indicating enhanced Aβ transit
from the brain to the periphery. Furthermore, both soluble and insoluble Aβ40 and
Aβ42 brain levels were decreased following GI254023X treatment, but these effects
lacked statistical significance.<br>
CONCLUSIONS: These studies demonstrate a role for ADAM10 in the ectodomain
shedding of LRP1 in the brain and the clearance of Aβ across the BBB, which may
provide a novel strategy for attenuating Aβ accumulation in the AD brain.
<br>
3. PLoS One. 2016 Apr 4;11(4):e0152921. doi: 10.1371/journal.pone.0152921.
eCollection 2016.
<br>
ADAM10 Is Involved in Cell Junction Assembly in Early Porcine Embryo Development.
<br>
Kwon J(1), Jeong SM(1), Choi I(2), Kim NH(1).
<br>
Author information: <br>
(1)Department of Animal Sciences, Chungbuk National University, Naesudong-ro,
Seowon-gu, Cheongju-si, Chungcheongbuk-do, 28864, Republic of Korea.
(2)Department of Animal and Dairy Sciences, College of Agriculture and Life
Sciences, Chungnam National University, Daejeon, 34134, Republic of Korea.
<br>
ADAM10 (A Disintegrin and Metalloprotease domain-containing protein 10) is a cell
surface protein with a unique structure possessing both potential adhesion and
protease domains. However, the role of ADAM10 in preimplantation stage embryos is
not clear. In this study, we examined the expression patterns and functional
roles of ADAM10 in porcine parthenotes during preimplantation development. The
transcription level of ADAM10 dramatically increased from the morula stage
onward. Immunostaining revealed that ADAM10 was present in both the nucleus and
cytoplasm in early cleavage stage embryos, and localized to the apical region of
the outer cells in morula and blastocyst embryos. Knockdown (KD) of ADAM10 using
double strand RNA did not alter preimplantation embryo development until morula
stage, but resulted in significantly reduced development to blastocyst stage.
Moreover, the KD blastocyst showed a decrease in gene expression of adherens and
tight junction (AJ/TJ), and an increase in trophectoderm TJ permeability by
disrupting TJ assembly. Treatment with an ADAM10 specific chemical inhibitor,
GI254023X, at the morula stage also inhibited blastocyst development and led to
disruption of TJ assembly. An in situ proximity ligation assay demonstrated
direct interaction of ADAM10 with coxsackie virus and adenovirus receptor
(CXADR), supporting the involvement of ADAM10 in TJ assembly. In conclusion, our
findings strongly suggest that ADADM10 is important for blastocyst formation
rather than compaction, particularly for TJ assembly and stabilization in
preimplantation porcine parthenogenetic development.
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