PGAM1
Phosphoglycerate mutase 1 (EC 5.4.2.11) (EC 5.4.2.4) (BPG-dependent PGAM 1) (Phosphoglycerate mutase isozyme B) (PGAM-B) [PGAMA] [CDABP0006]
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
MeSH Terms
- Alcohol Drinking
- Alzheimer Disease
- Amyloid beta-Protein Precursor
- Animals
- Behavior, Animal
- Brain
- Disease Models, Animal
- Mice, Transgenic
- tau Proteins
Keywords
- Aging
- Amyloid beta
- Ethanol
- GSK
- Immunohistochemistry
- Morris Water Maze
- Prepulse inhibition
- Self-administration
- Tau pathology
- Transgenic mouse model
To explore associated proteins involved in age-related changes of the testis and better understand the roles of these proteins in the human testis. We used two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spec trometry analysis to identify differentially expressed proteins between the aged and the normal control groups. The L-lactate dehydrogenase C chain (LDHC) protein, a previous testis-specific protein, was found to be downregulated in the aged testis and was further tested with western blot and immunohistochemical analysis to verify the result of the LDHC protein in 2-DE. Twelve differentially expressed proteins were identified. Among those proteins, 3 were upregulated and 9 were downregulated in the aged group. The results of western blot and immunohistochemical analysis confirmed the expression of LDHC downregulation in the aged testis. Some proteins identified had little well-known function in the human testis, as follows: AKR7A3, FDXR, PGAM1, SEPT2 and HMGCS2. Our results imply that the aged testis can be a good model to find associated proteins involved in age-related changes of the testis. It can be useful to understand the roles of those proteins in the testis.
MeSH Terms
- Aged
- Aging
- Down-Regulation
- Electrophoresis, Gel, Two-Dimensional
- Humans
- Immunohistochemistry
- Isoenzymes
- L-Lactate Dehydrogenase
- Male
- Middle Aged
- Proteins
- Proteomics
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
- Testis
- Young Adult