The Extensive Nitration of Neurofilament Light Chain in the Hippocampus Is Associated with the Cognitive Impairment Induced by Amyloid β in Mice

Abstract

Tyrosine nitration of proteins at an extensive level is widely associated with the cognitive pathology induced by amyloid ␤ peptide (A␤). However, the precise identity and explicit consequences of protein nitration have scarcely been addressed. In this study, we examined the detectable nitration of proteins in the hippocampus of mice with cognitive impairment (day 5) induced by the i.c.v. injection of A␤ 25-35 (day 0). The intensity of the nitration of proteins was inversely associated with the level of recognition memory in mice. The detectable tyrosine nitrations were revealed in proteins with a single size of approximately 70 kDa. The specific nitrated proteins at this size were identified using the liquid chromatography/mass spectrometry/ mass spectrometry analysis and immunodetection methods. Intense nitration of the neurofilament light chain (NFL) was observed. The increased nitration of NFL was associated with its serine hyperphosphorylation and weak interaction with the nuclear distribution element-like, a protein essential for the stable assembly of neurofilaments. No changes in cell numbers in the hippocampus were found (day 5) in mice that received A␤ [25][26][27][28][29][30][31][32][33][34][35] injections. These findings suggested that extensive nitration of NFL is associated with the A␤-induced impairment of recognition memory in mice.Increased nitration of proteins, a surrogate marker of widespread oxidative damage in brains affected by the amyloid ␤ peptide (A␤), is evidently correlated with the severity of cognitive dysfunction in humans as well as animals (Smith et al

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…At 1 week after injection, A␤ [25][26][27][28][29][30][31][32][33][34][35] induced significant oxidative stress in the hippocampus, as reflected by measured increases in lipid peroxidation, protein nitration, and superoxide generation. [11][12][13]40 In the present study, the early increases in lipid peroxidation levels observed after peptide injection were gradually reduced, particularly in the rat frontal cortex and amygdala, suggesting that oxidative stress could be alleviated by endogenous protective systems (putatively neurotrophins, such as BDNF).…”

“…brillary tangles (A␤ 25/26 -35 ) and in the degenerating hippocampal CA1 neurons with intracellular neurofibrillary tangles (A␤ [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] ), in AD brains, but not in agematched control subjects. 15 Deposits of A␤ [25][26][27][28][29][30][31][32][33][34][35] peptide after its injection have not yet been characterized by IHC, for lack of specific and selective antibodies.…”

Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease

“…The peptides were then administered by intracerebroventricular (i.c.v.) injection as described previously [37][38][39][40][41].…”

“…The reverse peptide, Aβ (Bachem) was prepared in the same way and used as a control. Both peptide stock solutions were incubated at 37°C for 4 days, to allow aggregation prior to administration [37]. The peptides were then administered by intracerebroventricular (i.c.v.)…”

Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice

“…In addition, tyrosine nitration contributes to Aβ-induced, and oxidative damage-mediated, cognitive dysfunction in rats and mice [29–32]. Recently, we have also demonstrated that tyrosine nitration of hippocampal proteins, specifically neurofilament light chain, correlates with the severity of cognitive impairments in mice [29,31]. …”