Nitrated amyloid enhances plaque formation in Alzheimer’s disease

in medicine

A group of scientists from Germany now reports that inflammation induced modification of the amyloid protein triggers plaque formation and postulate that this mechanism may be critical in Alzheimer's disease pathogenesis.

The incurable neurodegenerative disorder, Alzheimer's disease, causes progressive cognitive impairment and memory loss.  Alzheimer's disease (AD)  is characterized by loss of neurons and abnormal accumulation of amyloid Β (Abeta) protein plaques and neurofibrillary tangles of tau protein in the brain. Amyloid beta is a naturally processed fragment of the amyloid precursor protein.

The new study published in the September 8 issue of the journal Neuron identifies a previously unrecognized link between neuroinflammation and the classical pathological brain changes that are the hallmark of the disease. In addition, the research identifies a new potential therapeutic target for AD.

Neuroinflammation has been identified as a major component of the disease. Previous research has suggested that AD associated inflammation increases the inducible nitric oxide synthase (NOS2) in neurons and support cells. Importantly, NOS2 leads to generation of nitric oxide (NO) which has been linked with neurodegeneration.

Nitric oxide synthase catlyzes the production of nitric oxide from L-Arginine.

"One of the fingerprints of NO is tyrosine nitration, a posttranslational protein modification that can induce structural changes leading to protein aggregation," explains senior study author, Dr. Michael T. Heneka, from the University of Bonn in Germany. "Since there is so far no mechanistic explanation how expression of NOS2 and the subsequent production of NO and its reaction products modulate Abeta and thereby the progression of AD, we speculated that nitration of Abeta might contribute to AD pathology."

Though Abeta peptide is present in healthy tissues, the reason of its accumulation and plaque formation in brain has been unknown.

In their study, first author Dr. Markus P. Kummer and colleagues discovered that Abeta is a novel NO target. Though NO contributes to cell signaling by inducing posttranslational protein modifications, according to the findings reported in the paper, "under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide." They found that Abeta is nitrated by NO at tyrosine 10.

They observed nitrated Abeta in AD and AD mouse models and found that this modification accelerated the deposition of human Abeta. Importantly, reduction of NOS2 reduced Abeta deposition and memory deficits in a mouse model of AD. Further, nitrated Abeta induced the formation of amyloid plaques when injected into the brains of mice with genetic mutations associated with AD.

"Taken together, our results identify a novel modification of AΒ, tyrosine nitration, and propose a causative link between the AΒ cascade, activation of NOS2, and the subsequent increase in its reaction product nitric oxide during AD," concludes Dr. Heneka. "We think that nitrated AΒ may serve as marker of early AΒ 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."

Source article: Nitration of Tyrosine 10 Critically Enhances Amyloid β Aggregation and Plaque Formation. Neuron. 2011; 71(5) pp. 833 - 844. DOI: 10.1016/j.neuron.2011.07.001.
Additional source: Cell Press

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