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Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro
Annemieke A M Rensink1, Marcel M Verbeek, Irene Otte-Höller
1Department of Neurology, University Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. a.rensink@pathol.azn.nl
Insights
Catalase inhibits amyloid-beta (A beta) toxicity in human brain pericytes by binding and degrading A beta. This finding suggests targeting A beta assembly at the cell surface may reduce cerebral amyloid angiopathy.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Amyloid-beta (A beta) deposition in cerebral vasculature is a hallmark of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D).
- A beta(1-40) with the Dutch mutation (HCHWA-D A beta(1-40)) causes significant degeneration in cultured human brain pericytes.
Purpose of the Study:
- To identify inhibitors of A beta-induced toxicity in human brain pericytes.
- To investigate the mechanism by which catalase inhibits A beta toxicity.
Main Methods:
- Co-incubation of human brain pericytes with HCHWA-D A beta(1-40) and potential inhibitors (catalase, superoxide dismutase, glutathione, Trolox).
- Cell-free and cell culture assays to study catalase-A beta interactions.
- Analysis of A beta binding to the pericyte cell surface.
Main Results:
- Catalase, but not other tested agents, significantly inhibited HCHWA-D A beta(1-40)-induced pericyte degeneration.
- Catalase directly interacted with A beta in both cell-free and cell culture settings.
- Catalase influenced A beta's cell surface binding and conformational state, likely through direct A beta degradation rather than hydrogen peroxide conversion.
Conclusions:
- A beta assembly on the surface of human brain pericytes is critical for cellular degeneration.
- Catalase's inhibitory effect stems from its interaction with and degradation of A beta.
- Inhibiting A beta fibril formation at the cell surface represents a potential therapeutic strategy for cerebral amyloid angiopathy.
Abstract:
Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of cultured human brain pericytes. In this study, we aimed to identify inhibitors of A beta-induced toxicity in human brain pericytes. The toxic effect of HCHWA-D A beta(1-40) on human brain pericytes was inhibited by co-incubation with catalase, but not with superoxide dismutase, glutathione or vitamin E analogue Trolox. Catalase interacts with A beta, both in cell cultures and in cell-free assays, and has a prominent effect on the amount and conformational state of A beta binding to the cell surface of human brain pericytes. This activity of catalase is likely based on its ability to bind and slowly degrade A beta and not by its usual capacity to convert hydrogen peroxide. Our data confirm that assembly of A beta at the cell surface of human brain pericytes is a crucial step in A beta-induced cellular degeneration of human brain pericytes. Inhibition of fibril formation at the cell surface could be an important factor in therapy aimed at reducing cerebral amyloid angiopathy.
