Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids

Antonio Currais, Oswald Quehenberger, Aaron M Armando, Daniel Daugherty, Pam Maher and David Schubert

NPJ, Aging and Mechanisms of Disease, 2016, 2, 16012;

doi:10.1038/npjamd.2016.12; published online 23 June 2016

Nature Partner Journals;  www.nature.com/npjamd

 

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.

INTRODUCTION
Nerve cell death from the accumulation of aggregated or amyloidlike proteins is a common theme in most age-dependent neurodegenerative diseases. However, there are no drugs that significantly inhibit cell death associated with Alzheimer’s disease (AD), Parkinson’s or Huntington’s diseases. This could be because most interest has been in the late manifestations of the disease, not in the initial changes in cell metabolism that ultimately lead to nerve cell death.1 In the context of life span, slowing down the removal of aggregated proteins in the brains of flies shortens life span, while expediting their rate of removal extends life span.2

Therefore, it is likely that the accumulation of intracellular aggregated protein in the brain occurs throughout life, contributes to cognitive aging, and may also be involved in the initiation of many old age-associated diseases. Although debated,3,4 the accumulation of intracellular amyloid beta (Aβ) is an early event in AD. In both humans and rodents, intracellular Aβ accumulation is observed well before extracellular amyloid.5–8 Similarly, both aggregated huntingtin and alpha synuclein are found in neurons before disease onset.9,10 As with the accumulation of intracellular proteins, central nervous system (CNS) inflammation is elevated with age and increases in disease.11As AD is associated with neuronal dysfunction, we hypothesized that proteotoxicity in nerve cells themselves may initiate an inflammatory response that can lead directly to their death and contribute to overall inflammation in the CNS. The following experiments identify the molecular basis of this inflammatory response using a human CNS nerve cell line that conditionally expresses Aβ.

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