Limitations of the hCMEC/D3 cell line as a model for Aβ clearance by the human blood-brain barrier.

Alzheimer's disease and cerebral amyloid angiopathy are characterized by accumulation of amyloid-β (Aβ) at the cerebrovasculature due to decreased clearance at the blood-brain barrier (BBB). However, the exact mechanism of Aβ clearance across this barrier has not been fully elucidated. The hCMEC/D3 cell line has been characterized as a valid model for the BBB.

Inhibition of α-synuclein aggregation by small heat shock proteins.

The fibrillization of α-synuclein (α-syn) is a key event in the pathogenesis of α-synucleinopathies. Mutant α-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides α-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps).

Small heat shock proteins induce a cerebral inflammatory reaction.

More than 80% of Alzheimer's disease (AD) patients have some degree of cerebral amyloid angiopathy (CAA). In addition to arteries and veins, capillaries can also be affected. Capillary CAA (capCAA), rather than CAA in larger vessels, is associated with flame-like amyloid-beta (Aβ) deposits that may extend beyond the vessel wall and radiate into the neuropil, a phenomenon also known as "dyshoric angiopathy.

Do amyloid β-associated factors co-deposit with Aβ in mouse models for Alzheimer's disease?

Senile plaques and cerebral amyloid angiopathy in Alzheimer's disease (AD) patients not only consist of the amyloid-β protein (Aβ), but also contain many different Aβ-associated factors, such as heparan sulfate proteoglycans, apolipoproteins, and complement factors. These factors may all influence Aβ deposition, aggregation, and clearance and therefore seem important in the development of human Aβ deposits. To study AD pathology and test new therapeutic agents, many different mouse models have been created.

Enoxaparin treatment administered at both early and late stages of amyloid β deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain Aβ levels.

Enoxaparin (Enox), a low molecular weight heparin, has been shown to lower brain amyloid beta (A beta) load in a mouse model for Alzheimer's disease. However, the effect of Enox on cognition was not studied. Therefore, we examined the effect of peripheral Enox treatment on cognition and brain A beta levels in the APPswe/PS1dE9 mouse model by giving injections at an early (starting at 5 months of age) and late (starting at 10 and 12 months of age) stage of A beta accumulation for 3 months.

Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Abeta40 (DAbeta(1-40)) are modulated by sulfate moieties of heparin.

Glycosaminoglycans (GAGs), in particular as part of heparan sulfate proteoglycans, are associated with cerebral amyloid angiopathy (CAA). Similarly, GAGs are also associated with the severe CAA found in patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), where the amyloid beta (Abeta) peptide contains the Dutch mutation (DAbeta(1-40)). This suggests a role for GAGs in vascular Abeta aggregation.

Apolipoprotein E protects cultured pericytes and astrocytes from D-Abeta(1-40)-mediated cell death.

Cerebral amyloid angiopathy (CAA) is a common pathological finding in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type; in this latter condition it is caused by deposition of mutated amyloid beta protein (Abeta Glu22Gln; D-Abeta(1-40)). Previously, we found a dependence of the Abeta-mediated toxicity and apolipoprotein E (apoE) production by cultured pericytes on apoE genotype. Given their close association with the cerebrovascular wall both astrocytes and pericytes may be involved in CAA development, a process that includes Abeta deposition and clearance and that may be affected by interaction with locally produced apolipoprotein E (apoE).

Sulfation of heparan sulfate associated with amyloid-beta plaques in patients with Alzheimer's disease.

Alzheimer's disease (AD) is characterized by pathological lesions such as amyloid-beta (Abeta) plaques and cerebral amyloid angiopathy. Both these lesions consist mainly of aggregated Abeta protein and this aggregation is affected by macromolecules such as heparan sulfate (HS) proteoglycans. Previous studies demonstrated that HS enhances fibrillogenesis of Abeta and that this enhancement is dependent on the degree of sulfation of HS.

Metastatic dormancy imposed by the primary tumor: does it exist in humans?

Background: In cancer patients, occult micrometastases may become apparent shortly after removal of the primary tumor. Animal experiments have shown that metastatic dormancy is maintained by apoptosis, and that primary tumor removal induces a flare-up of angiogenesis, leading to metastatic outgrowth. This phenomenon has led to the hypothesis that the primary tumor generates certain factors that inhibit angiogenesis at distant sites.

Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.

Inefficient clearance of A beta, caused by impaired blood-brain barrier crossing into the circulation, seems to be a major cause of A beta accumulation in the brain of late-onset Alzheimer's disease patients and hereditary cerebral hemorrhage with amyloidosis Dutch type. We observed association of receptor for advanced glycation end products, CD36, and low-density lipoprotein receptor (LDLR) with cerebral amyloid angiopathy in both Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis Dutch type brains and increased low-density lipoprotein receptor-related protein-1 (LRP-1) expression by perivascular cells in cerebral amyloid angiopathy. We investigated if these A beta receptors are involved in A beta internalization and in A beta-mediated cell death of human cerebrovascular cells and astrocytes.

Heat shock proteins and amateur chaperones in amyloid-Beta accumulation and clearance in Alzheimer's disease.

The pathologic lesions of Alzheimer's disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular or extracellular misfolded proteins. The amyloid-beta (Abeta) protein accumulates extracellularly in senile plaques and cerebral amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. "Professional chaperones", such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent aggregation.

Small heat shock proteins associated with cerebral amyloid angiopathy of hereditary cerebral hemorrhage with amyloidosis (Dutch type) induce interleukin-6 secretion.

In hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), severe cerebral amyloid angiopathy (CAA) is associated with an inflammatory reaction. Small heat shock proteins (sHsps) are molecular chaperones and association of HspB8 with CAA in HCHWA-D has been observed. The aims of this study were to investigate (1) if other sHsps are associated with the pathological lesions in HCHWA-D brains, (2) if the amyloid-beta protein (A beta) increases production of sHsps in cultured cerebral cells and (3) if sHsps are involved in the cerebral inflammatory processes in both Alzheimer's disease (AD) and HCHWA-D.

Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators.

Background: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group.

Outgrowth of human liver metastases after resection of the primary colorectal tumor: a shift in the balance between apoptosis and proliferation.

Rapid outgrowth of metastases after removal of the primary tumor has been described in several mouse models. Loss of primary tumor-induced inhibition of angiogenesis in the metastases has been suggested as the underlying cause. Accordingly, we recently demonstrated that vascular density in human colorectal liver metastases increases after primary tumor resection.

Small heat shock proteins inhibit amyloid-beta protein aggregation and cerebrovascular amyloid-beta protein toxicity.

Small heat shock proteins Hsp20 and HspB2/B3 co-localize with Abeta deposition in senile plaques and cerebral amyloid angiopathy in Alzheimer's disease brains, respectively. It was the aim of our study to investigate if these and other sHsps bind to wild-type Abeta1-42 or the more toxic Abeta1-40 carrying the 'Dutch' mutation (22Glu-->Gln) (D-Abeta1-40), affect Abeta aggregation and thereby influence Abeta cytotoxicity. Binding affinity between sHsps and Abeta was investigated by surface plasmon resonance.

Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity.

Alzheimer's disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-beta precursor protein (APP), the amyloid-beta peptide (Abeta). CAA is also the major pathological lesion in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), caused by a mutation in the gene coding for the Abeta peptide. Several members of the small heat shock protein (sHsp) family, such as alphaB-crystallin, Hsp27, Hsp20 and HspB2, are associated with the pathological lesions of AD, and the direct interaction between sHsps and Abeta has been demonstrated in vitro.

Cerebral amyloid angiopathy with severe secondary vascular pathology: a histopathological study.

Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and is characterized by deposition of fibrillar amyloid in cortical and leptomeningeal vessels. In this study we describe the macroscopic and microscopic neuropathological findings of 5 patients with severe CAA-associated secondary vascular changes, including smooth muscle cell degeneration, hyalinization, 'double-barreling' phenomenon, macrophage infiltration, and aneurysmal dilatation of the vessel wall. In 3 of the 5 patients these vascular changes were associated with multiple small hemorrhages, whereas in 2 patients areas of ischemic necrosis were observed.

Plexin D1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy?

We previously reported that during mouse embryogenesis, plexin D1 (plxnD1) is expressed on neuronal and endothelial cells. Endothelial cells gradually loose plxnD1 expression during development. Here we describe, using in situ hybridization, that endothelial plxnD1 expression is regained during tumor angiogenesis in a mouse model of brain metastasis.

Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma.

Purpose: In primary uveal and cutaneous melanoma lesions, extracellular matrix (ECM) is often deposited in arcs, loops, and network patterns. Based on prognostic relevance, these patterns appear to play a significant role in facilitating metastasis. It has been demonstrated that these patterns were capable of transmitting fluid.

Apolipoprotein E genotype regulates amyloid-beta cytotoxicity.

The epsilon4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the epsilon2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes.

Decrease in circulating anti-angiogenic factors (angiostatin and endostatin) after surgical removal of primary colorectal carcinoma coincides with increased metabolic activity of liver metastases.

Removal of a primary colorectal tumor resulted in an increase in metabolic activity in its liver metastasis. Concomitantly, levels of angiostatin and endostatin in urine and plasma, respectively, dropped. This finding indicates that the primary tumor suppressed angiogenesis in its distant metastasis, and that removal of the primary lesion caused a flare-up in vessel neoformation and, thus, enhanced metabolic activity in its liver metastasis.

Progressive loss of endothelial P-selectin expression with increasing malignancy in colorectal cancer.

Adhesion of inflammatory cells to vascular endothelium is mediated by specific cell adhesion receptors on both leukocytes and endothelial cells. One of the adhesion molecules on the endothelium is P-selectin. Decreased vascular P-selectin expression has been associated with tumor progression in melanoma patients.

Absence of heparan sulfate proteoglycans in Lewy bodies and Lewy neurites in Parkinson's disease brains.

alpha-Synuclein is the major constituent of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Relatively little is known about the exact mechanism of alpha-synuclein deposition and fibrillization in these alpha-synucleinopathies. In order to better understand the pathogenesis of alpha-synucleinopathies it is important to identify molecules that regulate the fibrillization of alpha-synuclein.

Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients.

In animal models, explosive growth of metastases after removal of the primary tumor has been attributed to abolishment of angiogenesis inhibition. We investigated the influence of (removal of) the primary tumor on vascularization of liver metastases in human colorectal cancer patients. We analyzed vascular density in synchronous liver metastases from patients with the primary tumor in situ, in synchronous metastases from patients with the primary tumor resected and in metachronous metastases.