Sustained high levels of neuroprotective, high molecular weight, phosphorylated tau in the longest-lived rodent

Orr, Miranda E.; Garbarino, Valentina R.; Salinas, Angelica; Buffenstein, Rochelle

doi:10.1016/j.neurobiolaging.2014.12.004

Cited by 32 publications

(31 citation statements)

References 53 publications

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“…Approximately 50 mg frozen forebrain was used for subcellular fractionation and capillary electrophoresis as previously described (Orr et al, 2014; Orr, Garbarino, Salinas, & Buffenstein, 2015). Briefly, frozen tissue was powdered in liquid nitrogen and then homogenized with dounce and pestle and fractionated following manufacturer protocol (Subcellular Protein Fractionation Kit, Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…Tissues were then rinsed three times for 1–2 min in 50% ethanol. Following this step, tissue sections were transferred from 50% ethanol to TBS and proceeded to immunofluorescence staining as described previously (Orr et al, 2015, 2014 ). Primary antibodies used are as follows: PHF1 (1:100, kind gift from Dr. Peter Davies), NeuN (1:500 Cell Signaling, D3S31), and histone 3 (1:400, Cell Signaling, D1H2; Supporting Information Table S1).…”

Section: Methodsmentioning

confidence: 99%

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Tau protein aggregation is associated with cellular senescence in the brain

et al. 2018

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Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau‐containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT‐containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence‐like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late‐stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Tau protein aggregation is associated with cellular senescence in the brain

et al. 2018

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“…Of the brain regions examined, the hippocampus appears the least protected with low levels of HSP70, antioxidant capacity, and proteasome activity [123]. Despite this non-protective profile as well as high levels of beta amyloid (Aβ), a protein causally associated with Alzheimer’s disease [131] and phosphorylated tau [132], there is no overt evidence for neurodegenerative disease even in 30-year-old naked mole-rat brains. Further, antioxidant defenses seemingly do not account for the naked mole-rats’ ability to withstand oxidative damage (Table 1).…”

Section: Oxidative Stress and The Naked Mole-rat Tolerance To Hypoximentioning

confidence: 99%

Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates

Garbarino¹,

Orr

Rodriguez³

et al. 2015

Archives of Biochemistry and Biophysics

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The Oxidative Stress Theory of Aging has had tremendous impact in research involving aging and age-associated diseases including those that affect the nervous system. With over half a century of accrued data showing both strong support for and against this theory, there is a need to critically evaluate the data acquired from common biomedical research models, and to also diversify the species used in studies involving this proximate theory. One approach is to follow Orgel’s second axiom that “evolution is smarter than we are” and judiciously choose species that may have evolved to live with chronic or seasonal oxidative stressors. Vertebrates that have naturally evolved to live under extreme conditions (e.g., anoxia or hypoxia), as well as those that undergo daily or seasonal torpor encounter both decreased oxygen availability and subsequent reoxygenation, with concomitant increased oxidative stress. Due to its high metabolic activity, the brain may be particularly vulnerable to oxidative stress. Here, we focus on oxidative stress responses in the brains of certain mouse models as well as extremophilic vertebrates. Exploring the naturally evolved biological tools utilized to cope with seasonal or environmentally variable oxygen availability may yield key information pertinent for how to deal with oxidative stress and thereby mitigate its propagation of age-associated diseases.

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“…Recently we reported that brain tau phosphorylation decreased precipitously during the first 6 months of NMR postnatal life; nevertheless, they still expressed higher levels than mice (Orr et al, 2015). Since tau phosphorylation and expression signify different states of neuronal developmental maturity and stability (Goedert et al, 1989a,b; Kosik et al, 1989; Goedert and Jakes, 1990; Ksiezak-Reding et al, 1992; Bramblett et al, 1993; Brion et al, 1993; Kenessey and Yen, 1993; Köpke et al, 1993), we hypothesize that 6 months of age may mark a major milestone in NMR brain development.…”

Section: Introductionmentioning

confidence: 97%

“…Moreover, many of the described NMR brain features are suggestive of an extended period of development or persistent neoteny as well. These include blunted neuronal calcium response (Peterson et al, 2012a); sustained presence of the neurotrophic growth factor, neuregulin (Edrey et al, 2012); beta-amyloid (Edrey et al, 2013); phosphorylated tau (Orr et al, 2015); and neuroplasticity markers, doublecortin and PSA-NCAM (Penz et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Extended Postnatal Brain Development in the Longest-Lived Rodent: Prolonged Maintenance of Neotenous Traits in the Naked Mole-Rat Brain

Orr¹,

Garbarino

Salinas

et al. 2016

Front. Neurosci.

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The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan >31 years. Intriguingly, fully-grown naked mole-rats (NMRs) exhibit many traits typical of neonatal rodents. However, little is known about NMR growth and maturation, and we question whether sustained neotenous features when compared to mice, reflect an extended developmental period, commensurate with their exceptionally long life. We tracked development from birth to 3 years of age in the slowest maturing organ, the brain, by measuring mass, neural stem cell proliferation, axonal, and dendritic maturation, synaptogenesis and myelination. NMR brain maturation was compared to data from similar sized rodents, mice, and to that of long-lived mammals, humans, and non-human primates. We found that at birth, NMR brains are significantly more developed than mice, and rather are more similar to those of newborn primates, with clearly laminated hippocampi and myelinated white matter tracts. Despite this more mature brain at birth than mice, postnatal NMR brain maturation occurs at a far slower rate than mice, taking four-times longer than required for mice to fully complete brain development. At 4 months of age, NMR brains reach 90% of adult size with stable neuronal cytostructural protein expression whereas myelin protein expression does not plateau until 9 months of age in NMRs, and synaptic protein expression continues to change throughout the first 3 years of life. Intriguingly, NMR axonal composition is more similar to humans than mice whereby NMRs maintain expression of three-repeat (3R) tau even after brain growth is complete; mice experience an abrupt downregulation of 3R tau by postnatal day 8 which continues to diminish through 6 weeks of age. We have identified key ages in NMR cerebral development and suggest that the long-lived NMR may provide neurobiologists an exceptional model to study brain developmental processes that are compressed in common short-lived laboratory animal models.

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Sustained high levels of neuroprotective, high molecular weight, phosphorylated tau in the longest-lived rodent

Cited by 32 publications

References 53 publications

Tau protein aggregation is associated with cellular senescence in the brain

Tau protein aggregation is associated with cellular senescence in the brain

Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates

Extended Postnatal Brain Development in the Longest-Lived Rodent: Prolonged Maintenance of Neotenous Traits in the Naked Mole-Rat Brain

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