Age-related increase in the immunoproteasome content in rat hippocampus: molecular and functional aspects.
Alterations in the proteasome activity in the CNS have been described during aging. However, a detailed study of all proteasome subunits is actually lacking. We have analyzed, in vivo, the age-related modifications in the molecular composition of hippocampal proteasomes. We found that the immunoproteasome/proteasome ratio was increased in aged hippocampus. The processing of the low-molecular-mass protein (LMP)7/beta(5i) subunit, practically absent in young hippocampus, was increased in aged animals. Among the potential factors underlying these modifications we evaluated the neuroinflammation and the transcription factor Zif268. Lipopolysaccharide (LPS)-induced neuroinflammation in young rats, up-regulated the expression of immunoproteasome subunits and increased the processing of the LMP7/beta(5i) protein. Moreover, the hydrophobicity of cellular peptides, analyzed by liquid chromatography, increased in both, young LPS-injected animals and aged rats, suggesting that immunoproteasomes including the LMP7/beta(5i) subunit could, at least in part, account for this modification. Also, the mRNA expression of the transcription factor Zif268, which down-regulates the immunoproteasome subunit LMP7/beta(5i) by binding to sequences within the promoter regions, was decreased in both, aged hippocampus and young LPS-injected animals. Finally, we found that spatial memory training in young animals, a situation in which the expression of Zif268 is increased, modified the mRNA expression of the constitutive and catalytic subunits in an opposite manner. Based on present data, we propose that the age-related increases in the content of hippocampal immunoproteasome is mostly because of neuroinflammatory processes associated to aging.
Gavilán
M Paz
MP
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
Castaño
Angélica
A
Torres
Manuel
M
Portavella
Manuel
M
Caballero
Cristina
C
Jiménez
Sebastián
S
García-Martínez
Ana
A
Parrado
Juan
J
Vitorica
Javier
J
Ruano
Diego
D
D000375:Aging / Q000378:metabolism*; D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007136:Immunoglobulins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D021122:Protein Subunits; D012333:RNA, Messenger; C090698:SP1 antigen; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex