Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids

Abstract

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. Cannabinoids and other drugs that block inflammation in neurons could help thwart the progression of Alzheimer‘s disease. One of the hallmarks of this neurodegenerative disorder is the accumulation of clumps of amyloid-β protein within brain cells. Researchers led by David Schubert of the Salk Institute for Biological Studies in the USA used a tissue culture model to study the toxic effects of these protein aggregates. They determined that the production of amyloid-β initiates an inflammatory response that ultimately leads to neuronal death. However, the researchers also identified important protective mechanisms. For example, the brain produces compounds called endocannabinoids that help eliminate amyloid-β. Treatment with related chemical compounds like tetrahydrocannabinol–the active ingredient in marijuana–also reduced inflammation and prevented cell death, suggesting a potential avenue for preventing neurological damage from this devastating disease.