Nitration of Tyrosine 10 Critically Enhances Amyloid β Aggregation and Plaque Formation

Abstract

Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. 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. We identified amyloid β (Aβ) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-Aβ). Nitration of Aβ accelerated its aggregation and was detected in the core of Aβ plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-Aβ, overall Aβ deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-Aβ into the brain of young APP/PS1 mice induced β-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.

Phosphorylation Interferes with Maturation of Amyloid-β Fibrillar Structure in the N Terminus

“…The N-terminal region of A␤ is host for a wide range of events such as phosphorylation (23), metal binding (28,42), tyrosine nitration (43), and truncation (19,20). These events may modulate the role of A␤ in oxidative damage (44) and induction of inflammation (45) and alter the efficiency of prionlike self-propagation (24) and their interaction with biological targets such as cellular lipid membranes (46).…”

Thinking laterally about neurodegenerative proteinopathies

“…Notably, a large number of studies show that prionoids associated with CNS proteinopathies, when applied exogenously to glial cells, activate innate immunity through pattern recognition receptors and induce a proinflammatory response (50,53). Furthermore, there is some evidence that the resulting response to the DAMPs could modify the protein aggregate via various posttranslational modifications, such nitration, oxidation, or proteolysis, enhancing toxicity or promoting additional aggregation (54)(55)(56). Though studies of Aβ aggregates acting as DAMPs have until recently dominated this area of investigation, the finding that intracellular protein aggregates can be secreted provides a mechanism whereby even tau, α-synuclein, and other intracellular aggregates could activate the innate immune system upon secretion (57)(58)(59).…”

Cerium oxide nanoparticles protect against Aβ-induced mitochondrial fragmentation and neuronal cell death

“…1 Nitrosative stress caused by peroxynitrite has a critical role in the etiology and pathogenesis of AD. [2][3][4][5][6][7] Peroxynitrite is implicated in the formation of the two hallmarks of AD, Ab aggregates and neurofibrillary tangles containing hyperphosphorylated Tau protein. 1,4,7 In addition, peroxynitrite promotes the nitrotyrosination of presenilin 1, the catalytic subunit of the g-secretase complex, which shifts production of Ab to amyloid beta (Ab)42 and increases the Ab42/Ab40 ratio, ultimately resulting in an increased propensity for aggregation and neurotoxicity.…”

“…5 Furthermore, nitration of Ab tyrosine 10 enhances its aggregation. 6 Peroxynitrite can also modify enzymes, such as triosephosphate isomerase, 4 and activate kinases, including Jun amino-terminal kinase and p38 mitogen-activated protein kinase, which enhance neuronal cell death. 8,9 Moreover, peroxynitrite can trigger the release of free metals such as Zn 2 þ from intracellular stores with consequent inhibition of mitochondrial function and enhancement of neuronal cell death.…”