BAG3
BAG family molecular chaperone regulator 3 (BAG-3) (Bcl-2-associated athanogene 3) (Bcl-2-binding protein Bis) (Docking protein CAIR-1) [BIS]
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During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2-associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors NBR1, NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (-/-) mice. We also analyzed the levels of total tau and phospho-tau species. There were minimal differences in the expression of autophagy-related genes or tau species in 4-month-old animals; however, by 12 months, all of these autophagy-associated genes were expressed at significantly lower levels in the Nrf2 (-/-) mice. The decreases in the autophagy-associated genes were accompanied by significantly elevated levels of phospho-tau species in the 12-month-old Nrf2 (-/-) brains. These findings indicate that Nrf2 regulation of autophagy-related genes likely plays a greater role in mediating the clearance of tau as an organism ages.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Alzheimer Disease
- Animals
- Apoptosis Regulatory Proteins
- Autophagy
- Autophagy-Related Proteins
- Brain
- Gene Expression
- Mice, Inbred C57BL
- Mice, Knockout
- NF-E2-Related Factor 2
- Neurodegenerative Diseases
- tau Proteins
Keywords
- Autophagy adaptors
- BAG3
- Nrf2
- Tau
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Adipose Tissue
- Adult
- Aged
- Analysis of Variance
- Apolipoprotein A-I
- Apoptosis Regulatory Proteins
- Diabetes Mellitus, Type 2
- Enzyme-Linked Immunosorbent Assay
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Hypoglycemic Agents
- Insulin
- Male
- Middle Aged
- Nerve Growth Factors
- Neurons
- Obesity
- Pancreas
- Proto-Oncogene Proteins c-vav
- Reverse Transcriptase Polymerase Chain Reaction
- Synaptotagmins
Keywords
- age-related diabetes neuropathy
- aging
- diabetes
- obesity
- pancreas