Depending on its local concentration and its duration of release, nitric oxide (NO) can excert either protective or cell destructive actions on neurons. The inducible form of the enzyme responsible for the production of NO (inducible nitric oxide synthase or NOS2) is induced in glial cells and neurons during Alzheimer's disease (AD) and other neurodegenerative conditions (1,2). We have shown that the enzyme argininosuccinate synthase (ASS) delivering a substrate for iNOS is upregulated in the CNS under inflammatory conditions (3) and that neuronal expression of iNOS during AD is accompanied by ASS and GTPcH-I expression, which fosters a long term production of NO. In addition, we were able to demonstrate that that expression of iNOS and the resulting production of NO leads to apoptosis in differentiated PC12 cells and primary neurons (4).

Recently, we were able to demonstrate that a post-translational modification of a single tyrosine residue within amyloid β by NO, leads to the formation of 3-nitrotyrosine-Aβ (3NTyr10-Aβ), thereby initiating the tendency of amyloid β to form senile plaques and accelerates its aggregation (5). 3NTyr10-Aβ was found in the core senile plaques of both Alzheimer's patients and in a mouse model of Alzheimer's disease. Studies in a mouse model of Alzheimer's disease (APP/PS1-transgenic mice) show that loss of the NOS2 gene or oral treatment with the NOS2-inhibiting substance L-NIL decreased the amount of 3NTyr10-Aβ and thus the total amount of amyloid β and the protected the animals from learning deficits and memory loss. Since the administration of 3NTyr10-Aβ into the brain of young APP/PS1-mice triggers deposition of amyloid β, NOS2 inhibition may alter the progression of Alzheimer's disease and thus represents a potentially new therapeutic approach. In summary, we describe in the present study a previously unknown amyloid β species which is generated by tyrosine nitration and established a causal relationship between amyloid β formation and neuroinflammation. Nitrated amyloid β represents a promising therapeutic target for Alzheimer's disease and can be removed either by inhibition of nitric oxide synthase 2 as well as by specific vaccination.

1. M.T. Heneka, H. Wiesinger, L. Dumitrescu-Ozimek, P. Riederer, D.L. Feinstein and T. Klockgether (2001). Neuronal and glial expression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60: 906-79.

2. M.T. Heneka and D.L. Feinstein (2001). Function and expression of inducible nitric oxide synthase in neurons. J. Neuroimmunol. 114: 8-18.

3. M.T. Heneka, A. Schmidlin and H. Wiesinger (1999) Induction of argininosuccinate synthetase in rat brain glial cells after striatal microinjection of immunostimulants. J. Cereb. Blood Flow Met. 19: 898-907.

4. M.T. Heneka, P.-A. Löschmann, M. Gleichmann, M. Weller and T. Klockgether (1998) Induction of nitric oxide synthase (iNOS) and NO mediated apoptosis in neuronal PC12 cells after stimulation with TNFα/LPS. J. Neurochem. 71: 88-94.

5. Kummer, Markus P., Hermes, Michael, Delekate, Andrea, Hammerschmidt, Thea, Kumar, Sathish, Terwel, Dick, Walter, Jochen, Pape, Hans-Christian, König, Simone, Roeber, Sigrun, Jessen, Frank, Klockgether, Thomas, Korte, Martin and Heneka, Michael T. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron. 2011 Sep 8;71(5):833-44.

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