Neurofibrillary tangles (NFT) are a hallmark of
Alzheimer's disease. The major neurofibrillary tangle component is tau that is truncated at Asp421 (Deltatau), hyperphosphorylated and aggregates into insoluble paired helical filaments.
Alzheimer's disease brains also exhibit signs of
inflammation manifested by activated astrocytes and microglia, which produce
cytotoxic agents among them
prostaglandins. We show that
prostaglandin (PG) J2, an endogenous product of
inflammation, induces
caspase-mediated cleavage of tau, generating Deltatau, an aggregation prone form known to seed tau aggregation prior to neurofibrillary tangle formation. The initial event observed upon PGJ2-treatment of human
neuroblastoma SK-N-SH cells was the build-up of ubiquitinated (Ub)
proteins indicating an early disruption of the
ubiquitin-
proteasome pathway. Apoptosis kicked in later, manifested by
caspase activation and
caspase-mediated cleavage of tau at Asp421 and
poly (ADP-ribose) polymerase. Furthermore,
cathepsin inhibition stabilized Deltatau suggesting its lysosomal clearance. Upon PGJ2-treatment tau accumulated in a large perinuclear aggregate. In rat E18 cortical neuronal cultures PGJ2-treatment also generated Deltatau detected in dystrophic neurites. Levels of Deltatau were diminished by
caspase 3 knockdown using
siRNA.
PGD2, the precursor of
PGJ2, produced some Deltatau.
PGE2 generated none. Our data suggest a potential sequence of events triggered by the neurotoxic product of
inflammation PGJ2 leading to tau pathology. The accumulation of Ub
proteins is an early response. If cells fail to overcome the toxic effects induced by
PGJ2, including accumulation of Ub
proteins, apoptosis kicks in triggering
caspase activation and tau cleavage, the clearance of which by
cathepsins could be compromised culminating in tau pathology. Our studies are the first to provide a mechanistic link between
inflammation and tau pathology.