Mitochondrial dysfunction in platelets and hippocampi of senescence-accelerated mice

Xu, Jie; Shi, Chun; Li, Qi; Wu, Jiajia; Forster, E. Lucy; Yew, David T.

doi:10.1007/s10863-007-9077-y

Cited by 43 publications

(29 citation statements)

References 51 publications

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“…On the other hand, our results are in agreement with those authors who observed altered mitochondrial dysfunction in SAMP8 mice. For instance, Nishikawa et al (1998) detected an early stage mechanism underlying the age-associated mitochondrial dysfunction present in SAMP8 mouse brain, and Xu et al (2007) reported that platelet mitochondrial membrane potential as well as hippocampal and platelet ATP content in SAMP8 mice decreased at early age compared with SAMR1. Thus, our results support the contention that mitochondrial alterations may play a key role in the aging process.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…For instance, age-related changes in levels of antioxidant enzymes, such as copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese SOD (Mn-SOD), have been found in liver and cortex of SAMP8 mice when compared with age-matched SAMR1 mice, supporting increased oxidative stress as a key mechanism involved in the aging process (37). More recently, Yew and collaborators have shown an impairment of mitochondrial functions including a decrease of COX activity, mitochondrial ATP content, and mitochondrial glutathione (GSH) level at a relatively early age in SAMP8 mice compared with SAMR1 mice (67,78). Furthermore, the biochemical consequences of aging have been investigated using proteomic analysis in the brain of SAMP8 and SAMR1 mice at presymptomatic (5-month old) and symptomatic (15-month old) stages (84), revealing differentially expressed proteins with age in both mouse strains, such as Cu/Zn-SOD.…”

Section: Mitochondrial Aging-the Beginning Of the End In Ad?mentioning

confidence: 96%

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

Schmitt

Grimm

Kaźmierczak

et al. 2012

Antioxidants & Redox Signaling

123

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Significance: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-b [Ab]) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances: A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical Issues: In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Ab and tau in the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio ''aging, Ab, and tau protein'' triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation (OXPHOS), elevation of reactive oxygen species production, and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions: The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Ab and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon.

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“…Furthermore, increased levels of oxidative stress markers have been detected in younger (4-week-to 5-month-old) SAMP8 mice [30][31][32][33]. Mitochondrial dysfunction has also been demonstrated in SAMP8 mice in their younger period [34][35][36], although a decrease in ATP production was observed at a relatively later period (9-18 months of age) [36,37]. Taken together, these innate subtle abnormalities in the mitochondrial respiratory chain might cause a gradual accumulation of oxidative damage in vital macromolecules in the cells, which eventually results in brain dysfunction at an older age.…”

Section: A Higher Oxidative Stress Status Is a Primary Characteristicmentioning

confidence: 99%

The Senescence-accelerated Mouse (SAM): A Higher Oxidative Stress and Age-dependent Degenerative Diseases Model

et al. 2008

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The SAM strain of mice is actually a group of related inbred strains consisting of a series of SAMP (accelerated senescence-prone) and SAMR (accelerated senescence-resistant) strains. Compared with the SAMR strains, the SAMP strains show a more accelerated senescence process, a shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to human geriatric disorders. The higher oxidative stress status observed in SAMP mice is partly caused by mitochondrial dysfunction, and may be a cause of this senescence acceleration and age-dependent alterations in cell structure and function. Based on our recent observations, we discuss a possible mechanism for mitochondrial dysfunction resulting in the excessive production of reactive oxygen species, and a role for the hyperoxidative stress status in neurodegeneration in SAMP mice. These SAM strains can serve as a useful tool to understand the cellular mechanisms of age-dependent degeneration, and to develop clinical interventions.

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Mitochondrial dysfunction in platelets and hippocampi of senescence-accelerated mice

Cited by 43 publications

References 51 publications

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

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

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

The Senescence-accelerated Mouse (SAM): A Higher Oxidative Stress and Age-dependent Degenerative Diseases Model

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