Nitration of Amyloid beta Alzheimer 's disease

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Alzheimer's disease (AD) is characterized by the extracellular deposition of the amyloid beta (Abeta) peptide in senile plaques. Coming along with that is an neuroinflammation resulting in the increased production of the inducible form of the nitric oxide synthase 2 (NOS2) and its highly reactive product nitric oxide (NO), which is able to introduce post-translational modifications.One of these NO-mediated post-translational modification is the nitration of Abeta at tyrosine 10 (nitrated Abeta). This species is localized to the core of amyloid plaques in AD and is able to initiate the formation of plaques. Furthermore, ablation of NOS2 decreased Abeta deposition and cognitive dysfunction in an mouse model of AD (APP/PS1 mice).To understand the induction of NOS2 in AD and to test if early engagement with the formation of nitrated Abeta is a potential therapeutic approach, three objectives are proposed:1. To determine which cell types and brain areas express NOS2 and how this pattern is influenced by aging in wild type and in an AD mouse model.2. To reveal the spatial and temporal correlation of NOS2 expression in cells of the brain and the occurrence of plaques in APP/PS1 mice. We will determine whether core-containing amyloid plaques specifically develop at sites of NOS2 expression 3. To test if immunization against nitrated Abeta ameliorates the plaque pathology and the behavioral deficits in APP/PS1 mice. We will conduct passive and active immunization to improve the memory and learning phenotype and to reduce plaque in APP/PS1 mice.In the first and second objective, expression of NOS2 will be evaluated using a transgenic mouse that express a tdTomato and the CRE recombinase under the NOS2 promoter crossbred with a CRE-EYFP reporter mouse. Using this mouse it is possible to monitor transient as well as episodic expression of NOS2. Employing an in vivo-microscopy approach we will clarify if amyloid plaques appear at sites of previous and/or ongoing NOS2 expression. For passive immunization studies a new antibody against nitrated Abeta (4A4E8), recently developed in our laboratory, will be compared to an N-terminal Abeta antibody. Active immunization studies will be performed comparing the effect of a peptide comprising the nitrated Abeta epitope to the non-nitrated peptide. The effectiveness of the treatments will be monitored by testing memory and learning as well as changes in the plaque pathology.In this project a new and innovative therapeutic strategy for AD will be investigated by characterizing the early expression of NOS2 in AD and by conducting preventive immunizations using a post-translationally modified epitope of Abeta that only occurs under pathological conditions. This approach thus avoids the potential problem of autoimmunity in preventive immunizations against a peptide which function to this day is still unknown.