Proteomic analysis of brain proteins in APP/PS‐1 human double mutant knock‐in mice with increasing amyloid β‐peptide deposition: Insights into the effects of in vivo treatment with N‐acetylcysteine as a potential therapeutic intervention in mild cognitive impairment and Alzheimer's disease

Abstract

Proteomics analyses were performed on the brains of wild-type (WT) controls and an Alzheimer’s disease (AD) mouse model, APP/PS-1 human double mutant knock in mice. Mice were given either drinking water or water supplemented with N-acetylcysteine (NAC) (2mg/kg body weight) for a period of five months. The time periods of treatment correspond to ages prior to Aβ deposition (i.e., 4–9 months), resembling human mild cognitive impairment (MCI), and after Aβ deposition (i.e., 7–12 months), more closely resembling advancing stages of AD. Substantial differences exist between the proteomes of WT and APP/PS-1 mice at 9 or 12 months, indicating that Aβ deposition and oxidative stress lead to downstream changes in protein expression. Altered proteins are involved in energy-related pathways, excitotoxicity, cell cycle signaling, synaptic abnormalities, and cellular defense and structure. Overall, the proteomic results support the notion that NAC may be beneficial for increasing cellular stress responses in WT mice and for influencing the levels of energy- and mitochondrial related proteins in APP/PS-1 mice.

Neurodegeneration and Alzheimer's disease (AD). What Can Proteomics Tell Us About the Alzheimer's Brain?

“…Following treatment, some metabolic enzymes with reduced levels were increased. For instance, ␣-enolase and pyruvate kinase were reduced (suggesting that the oxidation of these proteins resulted in their degradation), whereas NAC significantly increased the levels of these enzymes (102). The discrepancies regarding the sign change of ␣-enolase in this Tg model, when compared with the AD brain, might be the result of the lack of neuronal cell death or strain differences because ␣-enolase was found to be increased in the brain of J20Tg mice (which is a double human APP mutant containing APP Swedish and Indiana mutations) (103), similar to the findings in human AD brain (Table I).…”

The 2013 SFRBM discovery award: Selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment

“…NAC treatment also led to decreased oxidative stress in this mouse model of AD as this antioxidant molecule did in the APP/PS-1 human double mutant knock-in mouse noted above, and proteomics identified brain proteins in this mouse that likely contributed to this neuroprotection following treatment with NAC [95]. …”

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

“…The release of glutamate from system x c Ϫ , especially the degree to which this causes activation of extrasynaptic NMDA receptors, may contribute to amyloid-␤ production and toxicity (Qin et al, 2006;Bordji et al, 2010). In contrast, cystine uptake by system x c Ϫ seems to exert powerful beneficial effects by lowering amyloid-␤-induced oxidative stress (Olivieri et al, 2001), reversing abnormal protein expression associated with a mouse model of Alzheimer's (Robinson et al, 2011), preventing apoptosis triggered by oxidative stress or a toxin implicated in Alzheimer's (Onyango et al, 2005a;Tanel and AverillBates, 2007), and normalizing the activity of sodiumdependent glutamate transporters (Begni et al, 2004). The last of these indicates the complexity of isolating the dual actions of system x c Ϫ and the need for additional work.…”