Abstract
BackgroundThe multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins.ResultsWe observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE) cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation.ConclusionThese data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.
Highlights
The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephritis
We recently reported that human ocular drusen contain nonfibrillar oligomers, which suggests that age-related macular degeneration may be another example of this type of amyloidosis [35], and a number of studies identify vitronectin as one of the most abundant drusen proteins [4,26,34,51]
Vitronectin deposits in senile plaques of Alzheimer brain In order to assess the presence of vitronectin in extracellular deposits, we examined Alzheimer disease brain
Summary
The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephritis. Vitronectin is a multi-functional glycoprotein involved in a variety of physiological processes. It is present in blood at a concentration of 0.2–0.45 mg/ml, constituting 0.1–. The multi-functional properties of vitronectin are mediated by its ability to interact with many other macromolecules. Vitronectin inhibits fibrinolysis through its N-terminal somatomedin B (SMB) domain, which binds to and stabilizes type 1 plasminogen activator inhibitor (PAI-1) [8,9]. Vitronectin associates with components of the extracellular matrix via a collagen-binding domain and a polycationic heparin-binding domain [11,12]. The C-terminal heparin-binding domain prevents complementmediated cell lysis by inhibiting assembly of the C5b-C9 membrane attack complex and blocking perforin pore formation [13,14,15]
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