P3.150 Microglial activation and age-related damage of dopaminergic neurodegeneration in MPTP-treated SAMP8 mice

AbstractBackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD.FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

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Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

Pharmaceuticals ◽

10.3390/ph14101040 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1040

Author(s):

Dolors Puigoriol-Illamola ◽

Júlia Companys-Alemany ◽

Kris McGuire ◽

Natalie Z. M. Homer ◽

Rosana Leiva ◽

...

Keyword(s):

Stress Responses ◽

Healthy Aging ◽

Molecular Mechanisms ◽

Chronic Mild Stress ◽

Mild Stress ◽

Cognitive Improvement ◽

Age Related ◽

Mtorc1 Signaling ◽

Cognitive Disturbances ◽

Samp8 Mice

Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer’s disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes—as well as pro-inflammatory mediators—through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD.

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Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

10.21203/rs.3.rs-72160/v1 ◽

2020 ◽

Author(s):

Andrés Fernández ◽

Elena Quintana ◽

Patricia Velasco ◽

Belén de Andrés ◽

Maria Luisa Gaspar ◽

...

Keyword(s):

Choroid Plexus ◽

Inflammatory Cytokines ◽

Hippocampal Formation ◽

Morphological Changes ◽

Interleukin 1 ◽

Brain Parenchyma ◽

Age Related ◽

Inflammatory Changes ◽

Samp8 Mice ◽

The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

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The Antioxidant Resveratrol from Polygonum Cuspidatum Reverses Memory Impairment and Brain Oxidative Stress in SAMP8 Mice

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.422.470 ◽

2011 ◽

Vol 422 ◽

pp. 470-473

Author(s):

Gui Shan Liu ◽

Ze Sheng Zhang ◽

Bo Yang ◽

Wei He

Keyword(s):

Oxidative Stress ◽

Learning And Memory ◽

Open Field ◽

Field Test ◽

Memory Impairment ◽

Open Field Test ◽

Pharmacological Action ◽

Age Related ◽

Brain Oxidative Stress ◽

Samp8 Mice

Resveratrol (RVT) is a phytoalexin polyphenolic compound found in various plants, including grapes, berries and peanuts. Recently, studies have documented various health benefits of resveratrol including cardiovascular and cancer-chemopreventive properties. The aim of the present study was to demonstrate the effects of resveratrol on the learning and memory impairment. The senescence-accelerated mice (SAM) were introgastric gavage administrated resveratrol (25,100mg/(kg•bw)) for 60 days. The learning and memory behavior was assessed using open-field test while the parameters of oxidative stress assessed were malondialdehyde (MDA) and superoxide dismutases (SOD).The results showed that resveratrol significantly improved the learning and memory ability in open-field test. Further investigation showed that resveratrol restored SOD levels, but decreased MDA level in the mouce brain. These results indicated that the pharmacological action of RVT may offer a novel therapeutic strategy for the treatment of age-related conditions.

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A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2012/364684 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Shankar J. Chinta ◽

Subramanian Rajagopalan ◽

Abirami Ganesan ◽

Julie K. Andersen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Microglial Activation ◽

Nitrosative Stress ◽

Neurodegenerative Disorder ◽

Oxidative And Nitrosative Stress ◽

Prolyl Hydroxylases ◽

Age Related

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB’s ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cellsin vitroin conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction.In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB’s neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1.

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Effects of moderate exercise over different phases on age-related physiological dysfunction in testes of SAMP8 mice

Experimental Gerontology ◽

10.1016/j.exger.2013.05.063 ◽

2013 ◽

Vol 48 (9) ◽

pp. 869-880 ◽

Cited By ~ 27

Author(s):

Xiujun Zhao ◽

Yanqing Bian ◽

Yichong Sun ◽

Li Li ◽

Lixuan Wang ◽

...

Keyword(s):

Moderate Exercise ◽

Age Related ◽

Samp8 Mice

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Lactobacillus paracasei PS23 decelerated age-related muscle loss by ensuring mitochondrial function in SAMP8 mice

Aging ◽

10.18632/aging.101782 ◽

2019 ◽

Vol 11 (2) ◽

pp. 756-770 ◽

Cited By ~ 3

Author(s):

Li-Han Chen ◽

Shih-Yi Huang ◽

Kuo-Chin Huang ◽

Chih-Chieh Hsu ◽

Kuen-Cheh Yang ◽

...

Keyword(s):

Mitochondrial Function ◽

Lactobacillus Paracasei ◽

Muscle Loss ◽

Age Related ◽

Samp8 Mice

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Long-Term Feeding of a High-Fat Diet Ameliorated Age-Related Phenotypes in SAMP8 Mice

Nutrients ◽

10.3390/nu12051416 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1416

Author(s):

Hideaki Oike ◽

Yukino Ogawa ◽

Kayo Azami

Keyword(s):

Control Diet ◽

Active Phase ◽

Restricted Feeding ◽

Long Term Effects ◽

High Fat ◽

Night Time ◽

Age Related ◽

Nutritional Studies ◽

Samp8 Mice

High-fat diets (HFD) have been thought to increase the risk of obesity and metabolic syndrome, as well as shorten lifespan. On the other hand, chrono-nutritional studies have shown that time-restricted feeding during active phase significantly suppresses the induction of HFD-induced obesity in mouse model. However, the long-term effects of time-restricted HFD feeding on aging are unknown. Therefore, in this study, we set up a total of four groups: mutual combination of ad libitum feeding or night-time-restricted feeding (NtRF) and an HFD or a control diet. We examined their long-term effects in a senescence-accelerated mouse strain, SAMP8, for over a year. Hearing ability, cognitive function, and other behavioral and physiological indexes were evaluated during the study. Unexpectedly, SAMP8 mice did not show early onset of death caused by the prolonged HFD intake, and both HFD and NtRF retarded age-related hearing loss (AHL). NtRF improved grip strength and cognitive memory scores, while HFD weakly suppressed age-related worsening of the appearance scores associated with the eyes. Notably, the HFD also retarded the progression of AHL in both DBA/2J and C57BL/6J mice. These results suggest that HFD prevents aging unless metabolic disorders occur and that HFD and NtRF are independently effective in retarding aging; thus, the combination of HFD and chrono-nutritional feeding may be an effective anti-aging strategy.

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