Session Title: Inflammation
PROSTAGLANDIN J2: A PRODUCT OF INFLAMMATION THAT CAUSES ALZHEIMER'S- AND PARKINSON'S-LIKE PATHOLOGY
Chronic inflammation is involved in the pathogenesis of Alzheimer's (AD) and Parkinson's (PD) diseases. However, there is a profound gap in the understanding of how pro-inflammatory cyclooxygenases and their prostaglandin products redirect cellular events to promote neurodegeneration. The major prostaglandin in the CNS is prostaglandin D2, which is short lived and readily generates the biologically active cyclopentenone J2 prostaglandins (PGJ2). PGJ2 are unique among prostaglandins because they are highly reactive and form Michael adducts with free thiol groups. PGJ2 can covalently modify glutathione and cysteines in cellular proteins. Electrophile binding by endogenous compounds such as PGJ2 is currently regarded as playing an important role in determining whether neurons will live or die. Our studies show that PGJ2 is potently neurotoxic, inhibits 26S proteasome and UCH-L1 activities, induces the accumulation/aggregation of ubiquitinated proteins, perturbs the cytoskeleton and up-regulates cyclooxygenase-2 in neuronal cell cultures. These changes are common to AD- and PD-pathology. Our data with neuronal cells further demonstrate that PGJ2 induces caspase-mediated cleavage of tau, generating Δtau(Asp421), an aggregation prone form that seeds tau aggregation prior to NFT formation in AD. We also modeled sporadic PD in mice by subchronic infusion of PGJ2 into the substantia nigra. The mice exhibited loss of dopaminergic neurons, accumulation/aggregation of ubiquitinated proteins and α-synuclein in dopaminergic neurons, microglia and astrocyte activation as well as posture and locomotor impairment. We propose that covalent binding of PGJ2 to proteins in the brain represents a novel pathogenic post-translational modification that plays a critical role in AD and PD neurodegeneration.