Abstract
The deleterious effects of aging on the brain remain to be fully elucidated. In the present study, proteomic changes of young (4-month) and aged (16-month) B6129SF2/J male mouse hippocampus and cerebral cortex were investigated by using nano liquid chromatography tandem mass spectrometry (NanoLC-ESI-MS/MS) combined with tandem mass tag (TMT) labeling technology. Compared with the young animals, 390 hippocampal proteins (121 increased and 269 decreased) and 258 cortical proteins (149 increased and 109 decreased) changed significantly in the aged mouse. Bioinformatic analysis indicated that these proteins are mainly involved in mitochondrial functions (FIS1, DRP1), oxidative stress (PRDX6, GSTP1, and GSTM1), synapses (SYT12, GLUR2), ribosome (RPL4, RPS3), cytoskeletal integrity, transcriptional regulation, and GTPase function. The mitochondrial fission-related proteins FIS1 and DRP1 were significantly increased in the hippocampus and cerebral cortex of the aged mice. Further results in the hippocampus showed that ATP content was significantly reduced in aged mice. A neurotrophin brain-derived neurotrophic factor (BNDF), a protein closely related with synaptic plasticity and memory, was also significantly decreased in the hippocampus of the aged mice, with the tendency of synaptic protein markers including complexin-2, synaptophysin, GLUR2, PSD95, NMDAR2A, and NMDAR1. More interestingly, 8-hydroxydeoxyguanosine (8-OHdG), a marker of DNA oxidative damage, increased as shown by immunofluorescence staining. In summary, we demonstrated that aging is associated with systemic changes involving mitochondrial dysfunction, energy reduction, oxidative stress, loss of neurotrophic factor, synaptic proteins, and ribosomal proteins, as well as molecular deficits involved in various physiological/pathological processes.
Highlights
Molecular and cellular changes occurring with the passage of time provide an indispensable foundation with which to detect and define deviations from the normal aging process that surfaces in the form of various neurodegenerative diseases [1, 2]
Our results showed that aging accompanying protein changes are related to mitochondrial dynamics, energy metabolism, GTPase function, oxidative stress, ribosome, synapses, loss of neurotrophic factor, and transcriptional regulation, among others
By using the LC-MS/MS analysis combined with tandem mass tag (TMT) labeling technology, based on two unique peptides, we identified a total of 3530 proteins in the hippocampus and cerebral cortex with a false discovery rate (FDR) of less than 1% (Figure 2(c))
Summary
Molecular and cellular changes occurring with the passage of time provide an indispensable foundation with which to detect and define deviations from the normal aging process that surfaces in the form of various neurodegenerative diseases [1, 2]. Several studies of physiological brain aging in mice have been published, some of which have examined gene expression changes and, more recently, proteomic differences. These studies have employed mice of various strains (BALB/c, C57BL/6NHsd, and C57BL/10J), ages (range of 1-30 months), and sexes (males, females, or both), with comparisons variably among various brain areas of the cerebral cortex, hypothalamus, and cerebellum [4,5,6,7,8,9,10]. Our results showed that aging accompanying protein changes are related to mitochondrial dynamics, energy metabolism, GTPase function, oxidative stress, ribosome, synapses, loss of neurotrophic factor, and transcriptional regulation, among others
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