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

• Published in: Proteomics (Weinheim) 2011-11, Vol.11 (21), p.4243-4256
• Main Authors: Robinson, Renã A. S., Joshi, Gururaj, Huang, Quanzhen, Sultana, Rukhsana, Baker, Austin S., Cai, Jian, Pierce, William, St. Clair, Daret K., Markesbery, William R., Butterfield, D. Allan
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Acetylcysteine - therapeutic use; Age; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Analytical, structural and metabolic biochemistry; Animal models; Animal proteomics; Animals; APP/PS1; beta -Amyloid; Biological and medical sciences; Body weight; Brain; Brain - drug effects; Brain - metabolism; Cell cycle; Cognitive ability; Cognitive Dysfunction - drug therapy; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drinking water; Excitotoxicity; Free Radical Scavengers - pharmacology; Free Radical Scavengers - therapeutic use; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Knock-In Techniques; Geriatrics; Humans; Medical sciences; Mice; Mild cognitive impairment; Miscellaneous; Mitochondria; Mutation; N-Acetylcysteine; Neurodegenerative diseases; Neurology; Oxidative stress; Presenilin-1 - genetics; Presenilin-1 - metabolism; Protein oxidation; Proteins; Proteome - genetics; Proteome - metabolism; Proteomics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Signal transduction; Therapeutic applications
• ISSN: 1615-9853; 1862-8346; 1615-9861
• DOI: 10.1002/pmic.201000523

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) (2 mg/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 mitochondria‐related proteins in APP/PS‐1 mice.