Proteomic Profile of Mouse Brain Aging Contributions to Mitochondrial Dysfunction, DNA Oxidative Damage, Loss of Neurotrophic Factor, and Synaptic and Ribosomal Proteins

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.

Construction of Unified Human Antimicrobial and Immunomodulatory Peptide Database and Examination of Antimicrobial and Immunomodulatory Peptides in Alzheimer’s Disease Using Network Analysis of Proteomics Datasets

“…Besides B2M, FAU's level dropped in the brain and of VGF in both brain and CSF. The data published in the scientific literature present elevated B2M and FAU levels in the brain and propose them as potential targets for AD therapy (Smith et al, 2015;Matthes et al, 2018;Li et al, 2020). Regarding TAC1 and VGF, our data are in accordance with the previously published data: neuropeptides derived from TAC1 exert a neuroprotective role in AD (Chen et al, 2019), and the VGF was discovered in mouse model as a key driver gene/protein.…”

RETRACTED: Abnormal Mitochondria-Endoplasmic Reticulum Communication Promotes Myocardial Infarction

“…The ER provides anchoring strength to promote mitochondrial contraction, while mitochondrial fission factors such as mitochondrial fission 1 (Fis1), dynamin-related protein 1 (Drp1), mitochondrial fission factor (Mff), mitochondrial dynamics protein of 49 kDa (Mid49) and mitochondrial dynamics protein of 51 kDa (Mid51) perform the contraction ( Zhou et al, 2018b ; Lobo-Gonzalez et al, 2020 ). Among these proteins, Fis1 is thought to contribute to myocardial infarction ( Cheng et al, 2020 ), as Mdivi-1 treatment significantly reduced the infarcted area by preventing Fis1 from binding to Drp1 ( Jannuzzi et al, 2020 ; Li et al, 2020 ). Recently, the binding between mitochondria-localized Fis1 and ER-expressed B cell receptor associated protein 31 (BAP31) was reported to stimulate mitochondria-dependent apoptosis by bridging the mitochondria-ER interface ( Iwasawa et al, 2011 ).…”

Acyl-CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

“…However, the pathway analysis of genes changed by age only in the Acsl6 –/– mice revealed additional reductions in genes related to axonal guidance and mitochondria ( Supplemental Figure 2 ). Moreover, numerous ribosomal protein genes were reduced in Acsl6 –/– mice by aging ( Figure 5D ), a hallmark of natural aging ( 33 , 34 ). An analysis of genes changed using both Reactome and Gene Ontology (GO) term enrichment analyses revealed that aged Acsl6 –/– mice, when compared with aged controls, had increased responses to stress and of the immune system and reduced membrane-related and synaptic proteins ( Figure 5E and Supplemental Figure 2 ).…”