Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM)

Canudas, Anna Maria; Gutiérrez‐Cuesta, Javier; Rodriguez, Maria-Luisa; Acuña-Castroviejo, Darı́o; Sureda, Francesc X.; Camins, Antoni; Pallàs, Mercè

doi:10.1016/j.mad.2005.07.008

Cited by 133 publications

(115 citation statements)

References 26 publications

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“…Recently, several authors reported an age-dependent pattern of glial tau aggregation in both human and baboon brains (Schultz et al, 2000;Yang et al, 2005b). Previous studies have shown that hyperphosphorylation of tau occurs in the brain of SAMP8 mice at 5 months of age (Canudas et al, 2005;Sureda et al, 2006). Consistent with these data, the present study has demonstrated increased tau phosphorylation at Ser 199 and Ser 396 in SAMP8 astrocyte cultures obtained from neonate brain, as compared with those of SAMR1 mice.…”

Section: Discussionsupporting

confidence: 90%

“…Interestingly, the former exhibits agerelated learning and memory deficits, as well as β -amyloid-like deposits in the brain (Flood & Morley, 1998;Chen et al ., 2004). Furthermore, increases in hyperphosphorylated tau and cyclin-dependent kinase 5 (Cdk5) expressions and activation have also been detected in SAMP8 mice (Canudas et al ., 2005). For these reasons, SAMP8 mice are regarded as a suitable rodent model for studying the molecular mechanisms underlying cognitive impairment in aged subjects.…”

Section: Introductionmentioning

confidence: 98%

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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: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 98%

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

et al. 2008

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“…Indeed, recent studies provide a more in-depth understanding of tau phosphorylation dynamics in the SAMP8. As such, the data indicates that various forms of hyperphosphorylated tau are more present in SAMP8 than in SAMR1 [22,55].…”

Section: Histopathological Similarities In Samp8 and Admentioning

confidence: 72%

“…SAMP8 brains overproduce amyloid precursor protein (APP) and have increased phosphorylation of tau [36]. Notably, tau hyperphosphorylation increases occur as early as 5 months of age in SAMP8 [22,55], which suggests that this process is an integral part of aging and, like oxidative stress, an early event in AD. Indeed, recent studies provide a more in-depth understanding of tau phosphorylation dynamics in the SAMP8.…”

Section: Histopathological Similarities In Samp8 and Admentioning

confidence: 99%

“…Tau hyperphosphorylation in SAMP8 is mediated by AD-related mechanisms, such as increases in Cdk5 expression [55]. Moreover, treatments such as melatonin [57,58] and lithium chloride [59] that reduce Cdk5 and GSK3β activation and activation of the cdk5/p35 pathway at its cleavage to cdk5/p25, which are all key players in AD-related hyperphosphorylation of tau during aging and neurodegenerative diseases [4,60], lead to a reduction in tau hyperphosphorylation when administered to SAMP8.…”

Section: Histopathological Similarities In Samp8 and Admentioning

confidence: 99%

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Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Pallàs

2012

ISRN Cell Biology

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The causes of aging remain unknown, but they are probably intimately linked to a multifactorial process that affects cell networks to varying degrees. Although a growing number of aging and Alzheimer's disease (AD) animal models are available, a more comprehensive and physiological mouse model is required. In this context, the senescence-accelerated mouse prone 8 (SAMP8) has a number of advantages, since its rapid physiological senescence means that it has about half the normal lifespan of a rodent. In addition, according to data gathered over the last five years, some of its behavioral traits and histopathology resemble AD human dementia. SAMP8 has remarkable pathological similarities to AD and may prove to be an excellent model for acquiring more in-depth knowledge of the age-related neurodegenerative processes behind brain senescence and AD in particular. We review these facts and particularly the data on parameters related to neurodegeneration. SAMP8 also shows signs of aging in the immune, vascular, and metabolic systems, among others.

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HGF Mediates Clinical‐Grade Human Umbilical Cord‐Derived Mesenchymal Stem Cells Improved Functional Recovery in a Senescence‐Accelerated Mouse Model of Alzheimer's Disease

Jia

Cao²,

Zhai³

et al. 2020

Advanced Science

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Stem cells have emerged as a potential therapy for a range of neural insults, but their application in Alzheimer's disease (AD) is still limited and the mechanisms underlying the cognitive benefits of stem cells remain to be elucidated. Here, the effects of clinical‐grade human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) on the recovery of cognitive ability in SAMP8 mice, a senescence‐accelerated mouse model of AD is explored. A functional assay identifies that the core functional factor hepatocyte growth factor (HGF) secreted from hUC‐MSCs plays critical roles in hUC‐MSC‐modulated recovery of damaged neural cells by down‐regulating hyperphosphorylated tau, reversing spine loss, and promoting synaptic plasticity in an AD cell model. Mechanistically, structural and functional recovery, as well as cognitive enhancements elicited by exposure to hUC‐MSCs, are at least partially mediated by HGF in the AD hippocampus through the activation of the cMet‐AKT‐GSK3β signaling pathway. Taken together, these data strongly implicate HGF in mediating hUC‐MSC‐induced improvements in functional recovery in AD models.

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Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM)

Cited by 133 publications

References 26 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

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

HGF Mediates Clinical‐Grade Human Umbilical Cord‐Derived Mesenchymal Stem Cells Improved Functional Recovery in a Senescence‐Accelerated Mouse Model of Alzheimer's Disease

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