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Suppression of A beta-induced monocyte neurotoxicity by antiinflammatory compounds
K A Dzenko1, R B Weltzien, J S Pachter
1Department of Pharmacology, University of Connecticut Health Center, Farmington 06030, USA.
Abstract:
Previous work from this laboratory has demonstrated that prior exposure of peripheral blood monocytes (PBM) to aggregated beta-amyloid peptide (A beta), the major protein comprising the amyloid plaques characteristically present in the brain of Alzheimer disease (AD)-afflicted individuals, activates these cells to a neurotoxic state when co-cultured with brain tissue. In this report we extend these findings to further show that such A beta-induced PBM neurotoxicity can be inhibited by three differentially-acting antiinflammatory drugs, indomethacin, dexamethasone, and colchicine, which are typically used clinically to treat peripheral inflammatory disease. In addition, evidence is presented that these toxic effects are initiated, in large part, by soluble factors released from A beta-stimulated PBM. Our results suggest a rationale for antiinflammatory therapy in the treatment of AD.
Insights
Prior exposure to beta-amyloid (A beta) activates monocytes, causing neurotoxicity. Anti-inflammatory drugs like indomethacin, dexamethasone, and colchicine inhibit this A beta-induced neurotoxicity, suggesting a therapeutic approach for Alzheimer disease (AD).
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Alzheimer disease (AD) is characterized by amyloid plaques.
- Peripheral blood monocytes (PBM) exposed to aggregated beta-amyloid (A beta) become neurotoxic.
- This neurotoxicity occurs when PBM are co-cultured with brain tissue.
Purpose of the Study:
- To investigate the neurotoxic potential of A beta-activated PBM.
- To determine if anti-inflammatory drugs can inhibit A beta-induced PBM neurotoxicity.
- To identify the role of soluble factors in mediating A beta-induced PBM neurotoxicity.
Main Methods:
- Co-culture of PBM with brain tissue after A beta exposure.
- Treatment of A beta-stimulated PBM with indomethacin, dexamethasone, and colchicine.
- Analysis of soluble factors released from A beta-stimulated PBM.
Main Results:
- A beta-exposed PBM induced neurotoxicity in co-cultured brain tissue.
- Indomethacin, dexamethasone, and colchicine significantly inhibited A beta-induced PBM neurotoxicity.
- Soluble factors released from A beta-stimulated PBM were largely responsible for the observed neurotoxicity.
Conclusions:
- A beta-activated PBM contribute to neurotoxicity relevant to Alzheimer disease.
- Clinically used anti-inflammatory drugs demonstrate potential for treating AD.
- Targeting soluble factors from activated PBM may offer a therapeutic strategy for AD.