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Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease.

ABSTRACT: Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from Wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. In recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. In addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. With age, neurodegenerative changes in the brain of OXYS rats become amplified. We have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (A?PP), accumulation of ?-amyloid (A?), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMD-like retinopathy in OXYS rats is also accompanied by increased accumulation of A? in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD.

SUBMITTER: Stefanova NA

PROVIDER: S-EPMC3984313 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease.

Stefanova Natalia A NA Kozhevnikova Oyuna S OS Vitovtov Anton O AO Maksimova Kseniya Yi KY Logvinov Sergey V SV Rudnitskaya Ekaterina A EA Korbolina Elena E EE Muraleva Natalia A NA Kolosova Nataliya G NG

Cell cycle (Georgetown, Tex.) 20140217 6

Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from Wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain ...[more]

PMID: 24552807

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Project description:As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study).With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.For the 2 studies that collected data on A? levels (ADNI and AIBL), we estimate decline in a preclinical AD "A?-positive" placebo group and compare them with an "A?-negative" group. For the study that did not include data on A? levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-?4 and by clinical progression.In ADNI, A?-positive participants showed more decline than did A?-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P?=?.02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P?=?.01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P?=?.002). In the ADCS-PI study, APOE-?4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P?=?.01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P?=?.001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P?<?.001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% ? level, we project 80% power to detect effects in the range of ??=?0.467 to 0.733 on the ADCS-PACC.Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.

Project description:PURPOSE: To determine the age-related and the cataract-specific changes in the crystallin composition in lenses of accelerated-senescence OXYS (cataract model) and Wistar (control) rats. METHODS: The water soluble (WS) and insoluble (WIS) fractions of the lens proteins were separated; the identity and relative abundance of each crystallin in WS fraction were determined with the use of two-dimensional electrophoresis (2-DE) and Matrix-Assisted Laser Desorption Ionization-Time Of Flight (MALDI-TOF) mass spectrometry. All statistical calculations were performed using the software package Statistica 6.0 by factor dispersion analysis (ANOVA/MANOVA) and Newman-Keuls post-hoc test for comparison of group mean values. RESULTS: The WIS protein content increased significantly in the aged animal lenses; the WIS/WS ratio increases in approximately 8 times to the age of 62 weeks. The interstrain difference was insignificant in this experiment. 2-DE maps of the young rat lenses (3 weeks) showed single spots for each lens protein while in older lenses (12 and 62 weeks) each crystallin was presented by several spots. The abundance of ?A-?F-crystallins in WS fraction significantly decreases with age. A significant increase in the percentage abundance was also found for ?-crystallins and ?B2-crystallin from 3 to 12 weeks. The major differences between Wistar and OXYS lenses are the faster decay of the content of ?A-?F-crystallins in OXYS lenses, and the significant decrease of unmodified ?A-crystallin abundance in old OXYS lenses. CONCLUSIONS: The presented results demonstrate that the increase of the water-insoluble (WIS) protein fraction is rather age-specific than cataract-specific phenomenon. The major age-related changes in WS protein composition are the fast insolubilization of ?-crystallins, and the increase of ?B- and ?B2-crystallin abundance. The main interstrain differences, which could be attributed to the cataract-specific processes, are the faster decay of the content of ?-crystallins and the significant decrease of unmodified ?A-crystallin abundance in the OXYS lenses.

Dataset Information

Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease.

Publications

Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease.

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