The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ. It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell’s demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death. Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective. Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.
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Antonio Currais, Oswald Quehenberger, Aaron M Armando, Daniel Daugherty, Pam Maher & David Schubert; Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids; npj Aging and Mechanisms of Disease 2, Article number: 16012 (2016) doi:10.1038/npjamd.2016.12
© 2016 Antonio Currais, Oswald Quehenberger, Aaron M Armando, Daniel Daugherty, Pam Maher & David Schubert; This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license.