Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8)

Yanai, Shuichi; Endo, Shogo

doi:10.1016/j.bbr.2016.04.026

Cited by 43 publications

(37 citation statements)

References 89 publications

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“…m Spine density per 10 μm dendritic segment in GFP + secondary or tertiary dendrites in SAMR1 and SAMP8 animals treated with 0 mg/ kg/day mouse model with age-related brain dysfunction, in which NSPC proliferation and neurogenesis fall below control levels over time [69][70][71][72]. SAMP8 mice present behavioral impairments in object recognition and fear conditioning, compatible with hippocampal dysfunction, and disrupted circadian rhythm as young as 4 months of age, supporting their use as a model of circadian rhythm disturbances associated with pathological aging [73,74]. Indeed, we found that AM and PM CORT levels were significantly elevated in untreated SAMP8 compared to the genetically related but senescence-resistant SAMR1 mice [75] of the same age (Fig.…”

Section: Disruption Of Gc Oscillations In Accelerated Senescence-pronmentioning

confidence: 78%

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain

et al. 2019

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A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.

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Section: Disruption Of Gc Oscillations In Accelerated Senescence-pronmentioning

confidence: 78%

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain

et al. 2019

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“…This mouse strain is a spontaneous model of senescence that demonstrates age-related brain pathologies and cognitive loss (Tomobe and Nomura, 2009). The defective learning and memory capacities of SAMP8 mice have been shown in different experimental tasks, including hippocampus-based spatial learning and memory and object recognition tasks (Dobarro et al, 2013;López-Ramos et al, 2012;Miyamoto et al, 1986;Wang et al, 2009;Yanai and Endo, 2016). Pathological changes are mainly present in the hippocampal area and include the following: (i) reduced synaptic plasticity with impaired long-term potentiation (LTP) (López-Ramos et al, 2012;Taniguchi et al, 2015) and lower activation of plasticity pathways (Li et al, 2009;Lin et al, 2014);(ii) increased levels of hyperphosphorylated tau (p-tau) with tau-related enzyme disorder (Álvarez-García et al, 2006;Canudas et al, 2005;Dobarro et al, 2013); (iii) higher accumulation of amyloid β peptides (A ) (Dobarro et al, 2013;Kumar et al, 2009;Zhang et al, 2011) which would be caused by an abnormally elevated synthesis of Aβ protein precursor (AβPP) (Griñán-Ferré et al, 2016;Morley et al, 2000) in addition to disturbances in the blood-brain barrier (Banks et al, 2011); (iv) oxidative stress (Álvarez-García et al, 2006;Butterfield et al, 1997;Morley et al, 2012); and (v) increased inflammation (Álvarez-López et al, 2014;Griñán-Ferré et al, 2016;Tha et al, 2000).…”

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confidence: 99%

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

et al. 2017

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Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.

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“…Age‐dependent cognitive deficits in spatial learning and memory has been reported in both homozygous SAMP8 and 3xTg‐AD mouse models subjected to spatial orientation tasks, including the Morris water maze and the Barnes maze tests, leading to increased escape latencies and a higher number of errors before reaching the target hole (Cheng et al, ; Clark et al, ; Miyamoto, ; Sterniczuk et al, ; Yanai and Endo, ). In our study, using the Barnes maze, all groups of mice displayed progressively decreasing latencies during the 4 days of training, suggesting comparable spatial learning between groups at the age of 19 months.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a 3xTg‐AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background

Virgili

Lebbadi

Tremblay

et al. 2018

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No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses Aβ plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble Aβ40 and Aβ42 concentrations (Aβ40, +85%; Aβ42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher Aβ42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.

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Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8)

Cited by 43 publications

References 89 publications

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

Characterization of a 3xTg‐AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background

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