Dysfunction of astrocytes in senescence-accelerated mice SAMP8 reduces their neuroprotective capacity.
Early onset increases in oxidative stress and tau pathology are present in the brain of senescence-accelerated mice prone (SAMP8). Astrocytes play an essential role, both in determining the brain's susceptibility to oxidative damage and in protecting neurons. In this study, we examine changes in tau phosphorylation, oxidative stress and glutamate uptake in primary cultures of cortical astrocytes from neonatal SAMP8 mice and senescence-accelerated-resistant mice (SAMR1). We demonstrated an enhancement of abnormally phosphorylated tau in Ser(199) and Ser(396) in SAMP8 astrocytes compared with that of SAMR1 control mice. Gsk3beta and Cdk5 kinase activity, which regulate tau phosphorylation, was also increased in SAMP8 astrocytes. Inhibition of Gsk3beta by lithium or Cdk5 by roscovitine reduced tau phosphorylation at Ser(396). Moreover, we detected an increase in radical superoxide generation, which may be responsible for the corresponding increase in lipoperoxidation and protein oxidation. We also observed a reduced mitochondrial membrane potential in SAMP8 mouse astrocytes. Glutamate uptake in astrocytes is a critical neuroprotective mechanism. SAMP8 astrocytes showed a decreased glutamate uptake compared with those of SAMR1 controls. Interestingly, survival of SAMP8 or SAMR1 neurons cocultured with SAMP8 astrocytes was significantly reduced. Our results indicate that alterations in astrocyte cultures from SAMP8 mice are similar to those detected in whole brains of SAMP8 mice at 1-5 months. Moreover, our findings suggest that this in vitro preparation is suitable for studying the molecular and cellular processes underlying early aging in this murine model. In addition, our study supports the contention that astrocytes play a key role in neurodegeneration during the aging process.
García-Matas
Silvia
S
Department of Pharmacology and Toxicology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona, Spain.
Gutierrez-Cuesta
Javier
J
Coto-Montes
Ana
A
Rubio-Acero
Raquel
R
Díez-Vives
Cristina
C
Camins
Antoni
A
Pallàs
Mercè
M
Sanfeliu
Coral
C
Cristòfol
Rosa
R
D000375:Aging / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D019588:Aging, Premature / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000737:chemistry / Q000473:pathology* / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008806:Mice, Inbred AKR; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse