Dysfunction of astrocytes in senescence‐accelerated mice SAMP8 reduces their neuroprotective capacity

Abstract

SummaryEarly 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 senescenceaccelerated-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. Gsk3β β β β and Cdk5 kinase activity, which regulate tau phosphorylation, was also increased in SAMP8 astrocytes. Inhibition of Gsk3β β β β 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.

Expression of Methylthioadenosine Phosphorylase (MTAP) in Pilocytic Astrocytomas

“…We describe that nonneoplastic astrocytes had virtually a complete loss of MTAP expression as opposed to the adjacent neoplastic astrocytes. In experimental studies on dementia, MTAP overexpression has been related to senescence and loss of neuroprotective function compared to normal astrocytes [47,48] . We therefore hypothesized that the adjacent cells play an essential role in the establishment of boundaries to the growth of PAs by avoiding these cells from senescence, thereby maintaining their neuroprotective role.…”

Heterogeneous astrocytes: Active players in CNS

“…The senescent astrocytes-released TNF-a, IL-1b and IL-6 clearly increased in rat brain both in the cortex and striatum during aging (Campuzano et al 2009). The proinflammatory phenotype is also observed in the isolated astrocytes from cerebral cortex, hippocampus and striatum of aged rat brain (Garcia-Matas et al 2008;Xie et al 2003). C/EBPβ and NF-κB are critical transcription factors that mediate proinflammatory signals in the SASP of astrocytes (Cardinaux et al 2000;Lee et al 1998).…”

Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model

“…Astroglial dysfunction has been proposed to underlie various neurodegenerative diseases [27][28][29]. To investigate whether Aβ phagocytosis is altered in the APP/PS1 mouse brain, primary astrocytes were isolated from APP/PS1 mice.…”

“…Astrocytes are required for maintaining normal brain functions, and astroglial dysfunction has been implicated in various neurodegenerative diseases [27][28][29]. Specifically, in AD, glutamate metabolism and glucose uptake in astrocytes have been reported to be impaired [30,31].…”