In a new study published in the Sep 08 issue of the journal Neuron, researchers recognize the characteristic feature of Alzheimer’s disease (AD) by discovering the previously unrecognized association of neuroinflammation with classical pathological brain changes, which further led to the identification of a new potential therapeutic target for AD.
AD is a devastating neurodegenerative disorder characterized by an atypical buildup of neurofibrillary tangles of tau protein and amyloid -(A-) protein plaques in the brain, which eventually results in progressive cognitive impairment and memory loss. These conventional hallmarks are further accompanied by neuroinflammation, which has been recognized as a chief component of the disease. Previous research suggests that an increase in the levels of inducible nitric oxide synthase (NOS2) in neurons and support cells is caused by inflammation associated with AD. Notably, the generation of nitric oxide (NO), which has been linked with neurodegeneration, can be attributed to NOS2.
Senior study author, Dr. Michael T. Heneka, from the University of Bonn in Germany says, “One of the fingerprints of NO is tyrosine nitration, a posttranslational protein modification that can induce structural changes leading to protein aggregation. Since there is so far no mechanistic explanation how expression of NOS2 and the subsequent production of NO and its reaction products modulate A- and thereby the progression of AD, we speculated that nitration of A- might contribute to AD pathology.”
Through this study, first author Dr. Markus P. Kummer and colleagues discovered that a novel NO target would be A-. On observing AD mouse models as well as nitrated A- in AD, researchers found that an alteration advanced the human A- deposition. A significant observation made in the mouse model of AD was that a decrease in NOS2 declined A- deposition and memory deficits. In addition, when mice brains with AD genetic mutations were induced with nitrated A-, it led to the formation of amyloid plaques.
To conclude, Dr. Heneka said, “Taken together, our results identify a novel modification of A-, tyrosine nitration, and propose a causative link between the A- cascade, activation of NOS2, and the subsequent increase in its reaction product nitric oxide during AD. We think that nitrated A- may serve as marker of early A- plaque formation. More importantly, it may be a promising target for an AD therapy, and that application of specific inhibitors of NOS2 may therefore open a new therapeutic avenue in AD.”