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Joseph Conovaloff RENOUS Meeting February 10, 2014

Joseph Conovaloff RENOUS Meeting February 10, 2014. Neuroinflammation. AD is characterized by amyloid beta plaques and neurofibrillary tangles (tau) Also by neuroinflammation (astrocytes and microglia activation), but not as well studied Release cytokines, chemokines , and nitric oxide

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Joseph Conovaloff RENOUS Meeting February 10, 2014

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  1. Joseph Conovaloff RENOUS Meeting February 10, 2014

  2. Neuroinflammation • AD is characterized by amyloid beta plaques and neurofibrillary tangles (tau) • Also by neuroinflammation (astrocytes and microglia activation), but not as well studied • Release cytokines, chemokines, and nitric oxide • AD-associated neuroinflammation can increase nitric oxide synthase 2 (NOS2) in neurons, astrocytes, and microglia • NOS2 important for generation of NO (detrimental to mitochondria, leading to cell death)

  3. Nitric Oxide (NO) Effect • “One of the fingerprints of NO is tyrosine nitration, a posttranslational protein modification, resulting in the formation of 30-nitrotyrosine residues (Radi, 2004) that can induce structural changes leading to protein aggregation.” Aβ42 DAEFRHDSGY10EVHHQKLVFF20AEDVGSNKGA30IIGLMVGGVV40IA

  4. In vitro levels of Nitrated Aβ Conclusion: Aβ is nitrated at Y10.

  5. Levels of Aβ in AD Patients (Immunohistochemistry) • In AD patient, we see nitrated Aβ. • More Aβin samples of AD patients. • Of the Aβ seen in brains, more greater percentage nitrated in AD patients than in non-AD patients. • Nitration localized in center of plaque, but no quantification. Significance?

  6. Nitration of Aβ in APP/PS1 Mice • In mice models, nitration takes place very early (already noticeable at 5 months). • Exact area of nitrated Aβ no change with time. Ratio of nitrated Aβ to Aβ plaque decreases with time.

  7. Nitration by NOS2 (-/-) • In AD mice (APP/PS1) with NOS2 (-/-) knock-out, there are much lower levels of relative nitrated Aβ (74% reduction) • Shows that NOS2 plays a role, as expected, in nitrating Aβ

  8. Nitration at Y10 Enhances Aggregation • Previous work: N-terminal modifications seem to induce aggregation. Does nitration at Y10 do the same? Yes. • ThioT: binds amyloid aggregates

  9. Behavioral Protection • APP/PS1 L-NIL: therapeutic approach; treating plaque containing mice (7-12 months) with NOS2 inhibitor, L-NIL. • Looked at LTP in CA1 hippocampal neurons from mice at 4 months (plaques are formed and nitrated) • Potential to look at LTP at later time points?

  10. Conclusion • Aβ is nitrated at Tyr10. • NOS2 leads to nitration. • Aβ nitration enhances aggregation (not shown: enhances plaque formation as well) • In mice model, L-NIL rescued memory deficits • Future: more work on NOS2 in other animal models and potential for use in clinical trials

  11. Joseph Conovaloff RENOUS Meeting February 10, 2014

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