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.
Highlights
Nerve cell death from the accumulation of aggregated or amyloidlike proteins is a common theme in most age-dependent neurodegenerative diseases
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 lead to nerve cell death.[1]
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
Summary
Nerve cell death from the accumulation of aggregated or amyloidlike proteins is a common theme in most age-dependent neurodegenerative diseases. 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 expression of Aβ leads to the induction of an inflammatory pathway and caspase dependent cell death.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
