Rapid degeneration of cultured human brain pericytes by amyloid betha protein

Contains fulltext : 24754___.PDF (publisher's version ) (Open Access

Apolipoprotein E genotype regulates amyloid-beta cytotoxicity.

Contains fulltext : 48028.pdf (publisher's version ) (Open Access)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. Previously, we described that synthetic amyloid-beta1-40 peptide (Abeta1-40) with the 22Glu--> Gln "Dutch" mutation caused pericyte death in vitro by a mechanism that involves Abeta fibril-like assembly at the cell surface. It is known that ApoE binds to Abeta and may modify its biological activities. In the present study, we evaluated the effect of ApoE on Abeta-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an epsilon4/epsilon4 genotype were more vulnerable to Abeta than cultures with an epsilon3/epsilon3 or epsilon3/epsilon4 genotype. The one cell culture with the epsilon2/epsilon3 genotype was relatively resistant to Abeta compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against Abeta-mediated toxicity of cerebrovascular cells and, in addition, ApoE epsilon2/epsilon3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with epsilon4/epsilon4 cells. Thus, the disparity between ApoE genotype and Abeta-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of Abeta cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to Abeta and thereby modify Abeta-mediated cell death

Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein.

Contains fulltext : 48563.pdf (publisher's version ) (Closed access)Cerebral vascular amyloid beta-protein (Abeta) deposition, also known as cerebral amyloid angiopathy, is a common pathological feature of Alzheimer's disease. Additionally, several familial forms of cerebral amyloid angiopathy exist including the Dutch (E22Q) and Iowa (D23N) mutations of Abeta. Increasing evidence has associated cerebral microvascular amyloid deposition with neuroinflammation and dementia in these disorders. We recently established a transgenic mouse model (Tg-SwDI) that expresses human vasculotropic Dutch/Iowa mutant amyloid beta-protein precursor in brain. Tg-SwDI mice were shown to develop early-onset deposition of Abeta exhibiting high association with cerebral microvessels. Here we present quantitative temporal analysis showing robust and progressive accumulation of cerebral microvascular fibrillar Abeta accompanied by decreased cerebral vascular densities, the presence of apoptotic cerebral vascular cells, and cerebral vascular cell loss in Tg-SwDI mice. Abundant neuroinflammatory reactive astrocytes and activated microglia strongly associated with the cerebral microvascular fibrillar Abeta deposits. In addition, Tg-SwDI mouse brain exhibited elevated levels of the inflammatory cytokines interleukin-1beta and -6. Together, these studies identify the Tg-SwDI mouse as a unique model to investigate selective accumulation of cerebral microvascular amyloid and the associated neuroinflammation

Normal cerebrospinal fluid concentrations of PDGFRβ in patients with cerebral amyloid angiopathy and Alzheimer's disease

BACKGROUND: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRβ levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD). METHODS: CSF PDGFRβ levels were quantified by enzyme-linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRβ both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers. RESULTS: PDGFRβ levels were similar in CAA patients and controls (P = .78) and in aMCI/AD clinical phenotype and controls (P = .91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRβ levels compared to (A-T-[N-]) controls (P = .006). CONCLUSION: Our findings indicate that PDGFRβ levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome