ALZHEIMER
AMYLOID BETA PROTEIN UPTAKE BY VASCULAR SMC:
A central and constant feature of Alzheimer's disease (AD) is the accumulation
of neuritic plaques containing aggregates of amyloid beta (Abeta)
peptides derived from a larger amyloid precursor protein (APP). Although
theories differ on how Abeta accumulation leads to neurodegeneration
and other sequelae of AD, the discovery of specific mutations in the APP
gene in familial AD leaves little doubt that APP plays a central role in
the pathogenesis of this disorder, as well as in a closely related disorder
called cerebral amyloid angiopathy (CAA). In CAA, amyloidogenic proteins
(Abeta) accumulate in cortical and leptomeningeal blood vessel walls.
Recent data also establish that the apolipoprotein E (APOE) locus is associated
with an increased risk for sporadic and some familial forms of AD and CAA.
APOE is primarily involved in the transport of lipids and is a ligand for
at least three central nervous system receptors: low-density lipoprotein
receptor, very low-density lipoprotein receptor, and low-density lipoprotein-like
receptor. The APOE gene, which is located on human chromosome 19, has three
common alleles (epsilon2, epsilon3, epsilon4) that encode for three main
isoforms indicated as E2, E3, and E4, respectively. It is the E4 isoform
that enhances the risk of AD and CAA, whereas the E2 isoform may be protective.
Although APOE4 appears to bind to Abeta in vitro, the mechanism by
which it acts in vivo to exacerbate AD and CAA has remained a mystery. A
possible answer is revealed in this month's Laboratory Investigation by
Urmoneit and colleagues. Using primary cultures of smooth muscle cells (SMC)
from leptomeningeal vessels, they find that Abeta proteins are rapidly
internalized by receptor-mediated endocytosis, and that the receptor involved
is probably low-density lipoprotein receptor. They postulate that Abeta-APOE4
complexes, formed in the cerebrospinal fluid or extracellular fluid of the
brain, are internalized and accumulate in cerebrovascular SMC. The subsequent
death of these cells releases the aggregated Abeta as perivascular
fibrillar amyloid. Although their results do not prove that SMC degeneration
actually occurs, that amyloid fibrils are released from the SMC, or that
a similar process obtains in neurons, Urmoneit et al's hypothesis is tenable,
testable, and provocative.
ANTI-INTERLEUKIN 8 AND STROKE:
Acute arterial obstructions cause tissue injury in two phases. Initially,
the tissue is injured because it is deprived of nutrients and oxygen. Subsequently,
when blood perfusion is restored, injury can be exacerbated by free radical
reactions initiated by reactive oxygen intermediates (ROI). ROI are generated
by enzymatic reduction of molecular oxygen delivered to the tissue by the
restoration of blood flow, and this second phase is commonly called reperfusion
injury. In humans, the primary source of the enzymes that produce ROI are
infiltrating neutrophils. This has led to the notion, in current clinical
trials, that interventions reducing neutrophil recruitment into reperfused
tissues will also reduce the extent of reperfusion injury. Although there
is a reasonably good understanding of the adhesion molecules and neutrophil-activating
signals (eg, chemokines) involved in neutrophil recruitment and activation,
the relative importance of particular molecules may vary with the organ
and inflammatory stimulus. In this issue of the journal, Matsumoto and colleagues
have used a rabbit model of cerebral ischemia/reperfusion to show that a
neutralizing antibody to the chemokine IL-8 can reduce the magnitude of
cerebral edema and infarct size. This result supports the important role
played by neutrophils in ischemic stroke, and suggests that inhibition of
IL-8 secretion or action may be a good target for therapy in humans.
TARGETING OF ADENOVIRAL-MEDIATED
GENE TRANSFER:
Over the years, many investigators have determined that specific extracellular
matrix and cell surface molecules mediate interactions with specific infectious
agents, leading to cell, tissue, and organism pathology. For example, Staphylococcus
aureus utilize a fibronectin-binding protein to adhere to and invade tissue;
Pneumocystis carinii recognize and bind to the RGDS cell attachment sequence
on fibronectin, facilitating subsequent intracellular invasion by this organism;
Yersinia pseudotuberculosis utilizes a protein called invasin to interact
with cell beta1 integrins before intracellular invasion; intercellular adhesion
molecule-1 (ICAM-1) is the major human Rhinovirus receptor; and alphavbeta3
and alphavbeta5 are thought to be required for adenoviral internalization.
In their current paper, Delporte et al extend these observations, illustrating
a complex relationship between the cellular distribution of the alphavbeta3
and alphavbeta5 integrins on luminal membranes of ductal and acinar
cells and adenoviral infection of the salivary glands. Their results support
previous studies in this area and suggest that alphavbeta3/5-expressing
salivary glandular epithelial cells may be desirable targets for adenoviral-mediated
gene therapy using an intraductal administration route.
RENAL INJURY IN HGF TRANSGENIC
MICE:
Hepatocyte growth factor/scatter factor (HGF/SF) has been associated with
a broad range of biologic effects. The binding of HGF/SF to its tyrosine
kinase family receptor (Met) triggers cell dissociation, motility, and mitogenesis,
and has recently been specifically associated with renal tubulogenesis.
The factor is thought to be a signaling mechanism, produced by mesenchymal
cells and detected by epithelial cells. The receptor is expressed in a wide
range of epithelial cells, and especially in cells from tissues that undergo
physiologic architectural remodeling such as the mammary gland. In kidney,
kinase-activating mutations in the HGF/SF receptor are associated with papillary
renal cell carcinoma. In this issue, Takayama and colleagues describe the
production of a transgenic mouse that overexpresses HGF/SF in the kidney
and in serum. The resultant constitutive stimulation of this receptor, believed
to be an autocrine function, results in tubular cystic disease, glomerulosclerosis,
and ultimately renal failure, but does not affect developmental formation
of the kidneys or result in renal cell carcinoma. These findings raise the
possibility that autocrine stimulation of Met receptors results in a different
phenotype than that seen in carcinomas overexpressing Met, and raise several
caveats to the possible use of HGF/SF as a therapeutic agent to stimulate
tissue responses.
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