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Cerebrovasculature-mediated neuronal cell death
P Grammas1, U Reimann-Philipp, P H Weigel
1Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
Insights
Alzheimer's disease (AD) brain microvessels produce neurotoxins like nitric oxide, causing neuronal cell death. This suggests a novel vascular mechanism contributing to AD pathogenesis.
Area of Science:
- Neuroscience
- Vascular Biology
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) is increasingly linked to vascular disease.
- The ApoE genotype is a risk factor for both coronary artery disease and AD.
- Brain microvessels may contribute to AD pathogenesis by releasing neurotoxic factors.
Purpose of the Study:
- To investigate if Alzheimer's disease (AD) brain microvessels produce neurotoxic factors.
- To determine if AD microvessels can cause neuronal cell death in vitro.
- To explore the role of cerebral microvasculature in AD pathogenesis.
Main Methods:
- Microvessels were isolated from the cerebral cortices of AD patients and age-matched controls.
- Neurotoxicity was assessed by co-culturing microvessels with primary neurons (rat and human).
- Levels of nitric oxide and the effect of cycloheximide on protein synthesis were measured.
Main Results:
- Microvessels from AD brains produced significantly higher levels of nitric oxide compared to controls.
- AD microvessels induced dose-dependent neuronal cell death in co-culture experiments.
- Inhibition of protein synthesis in AD microvessels reduced their neurotoxic effect, indicating a protein-based toxin.
Conclusions:
- Cerebral microvessels in Alzheimer's disease (AD) patients produce neurotoxic factors.
- These factors, including nitric oxide, contribute to neuronal injury and cell death.
- Vascular-mediated neuronal damage represents a novel mechanism in AD pathogenesis.
Abstract:
The presence of significant vascular disease in patients with Alzheimer's disease (AD) and the recognition of the ApoE genotype as a risk factor for both coronary disease and AD support an association between AD and vascular disease. It is our hypothesis that brain microvessels contribute to the pathogenesis of AD by producing soluble factors that injure or kill neurons. In this study we report that AD microvessels produce factors that are noxious to neurons and that these vessels can evoke neuronal cell death in vitro. In these experiments, microvessels are isolated from the cerebral cortices of AD patients and non-demented elderly and young controls. Microvessels isolated from AD brains produce high levels of a known neurotoxin nitric oxide, compared to vessels from aged-matched controls. In addition, we demonstrate a direct neurotoxic effect of AD microvessels when co-cultured with primary rat cerebral cortical neurons. In contrast, vessels from elderly non-demented donors are less lethal, and brain vessels from younger donors are not neurotoxic. Similarly, AD vessels exhibit a dose-dependent toxicity in co-culture with the human neurons. Finally, treatment of AD microvessels with the protein synthesis inhibitor cycloheximide reduces AD vessel neurotoxicity, suggesting that the neurotoxic factor is a protein. These findings suggest that the cerebral microvasculature is a source of factors that can injure neurons and implicate a novel mechanism of vascular-mediated neuronal cell death in AD.