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Whole transcriptome analysis of brain hippocampal tissue from young and old senescence-accelerated prone SAMP8 mice treated with control diet and J147-containing diet

ABSTRACT: AD drug discovery has rarely been addressed in the context of aging even though sporadic AD accounts for 99% of the cases. Phenotypic screens based upon old age-associated brain toxicities were used to develop the potent AD drug candidate J147. Here, we hypothesized that J147 would be effective against both brain aging and AD-associated pathology in rapidly aging SAMP8 mice, a model for early sporadic AD. An inclusive and integrative multi-omics approach was used to investigate protein expression, RNA expression, metabolite levels as well as cognition in old and young SAMP8 mice. J147 not only reduced the cognitive deficits and associated metabolic changes observed in old SAMP8 mice, it restored the levels of multiple markers of AD, vascular pathology, synaptic function, and inflammation to those approaching the young phenotype. Our data show that a drug candidate selected upon the basis of preventing old age-related brain toxicities also reduces AD-associated pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE69244 | GEO | 2015/11/17

SECONDARY ACCESSION(S): PRJNA284955

REPOSITORIES: GEO

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Project description:Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related path- ways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mito- chondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. Key words: astrocytes; caloric restriction; mitochondria; oxidative stress; RNA microarrays; SAMP8. Primary cultures enriched in astrocytes were obtained from cerebral cortical tissue from 2-day-old SAMP8 and SAMR1 mice. Astrocyte cultures were established and experiments were routinely carried out after 21 days in culture. Established astrocyte cultures of both SAMR1 and SAMP8 consisted of 85-90% astrocytes, 10-15% microglia and 0.1-1% oligodendroglia. Sera from rats subjected to ad libitum (AL) diet and to CR were obtained as described for the establishment of the CR in vitro model (de Cabo et al., 2003). Serum was heat inactivated at 56°C prior to use in astrocyte culture experiments. Treatment in vitro was performed by adding 10% volume CR or AL serum onto the astrocyte culture medium for 48 h, the cells were harvested and RNA was extracted for the microarray studies. Three biological replicates for each condition were done and RNA was extracted for the microarray studies. Please note that SAM models were developed from AKR/J by Kyoto University. Five litters with severe senescence were selected to further propagate and examine these characteristics. Litters that showed normal aging were selected as a senescence-resistant series (R-series). The genetic background of the SAM mice became suspect after the pathological findings were different from the AKR/J mouse. Each SAM model is genetically different. Each SAM colony was acquired by Harlan by Takeda Chemical Ltd. in 2002. And here is the link to the company site. http://www.harlan.com/products_and_services/research_models_and_services/research_models/sam_inbred_mice/samp8tahsd.hl

Project description:The present study examines the effects of whale meat extract (WME) supplementation on the senescence-accelerated mouse prone 8 (SAMP8) model at the level of learning memory formation and gene expression profiles genome-wide. Our present study builds up on these previous studies by focusing on two sets of experiments examining WME-supplemented diet, on SAMP8 and SAMR1 (senescence-accelerated mouse resistant 1) learning and memory deficits (experiment 1) and whole-genome DNA microarray-based transcriptomics profiling in conjunction with Ingenuity Pathway Analysis (IPA) (experiment 2). We also examined the SAMP8 and SAMR1 mice fed with the regular (control; low-safflower oil, LSO) diets specifically to know the gene profiles in the brain of the SAMP8 mouse. Results revealed that WME supplementation on SAMP8 mouse resulted in an increase in the level of learning memory formation and positive changes in the transcriptome of the brain, suggested through the observation of recovery of gene expressions in the SAMP8 model over the not-supplemented mouse. 6-week-old mice (SAMP8 and SAMR1; CLEA, Tokyo, Japan) were housed at the Animal Institution Facility in Showa University, and maintained in individual cages in a ventilated animal room with controlled temperature and relative humidity under a 12-h light: 12-h dark regime (8:00 AM, lights turned on). Mice were fed chow (CE-2, CLEA Japan) and tap water ad libitum until 24-weeks-old. Then, 24-week-old SAMs mice were given experimental diet, LSO diet as a control diet and WME-supplemented diet, both in a powder form. The WME was made from red meat of Antarctic minke whale (Balaenoptera bonaerensis), taken from the Japanese Whale Research Program under Special Permit in the Antarctic-Phase II in 2009/2010 by heat, enzyme and drying treatments. The quality standard of WE were measured by Marugei Co. Ltd. (Hyogo, Japan). SAMP8 mice were randomly given LSO or WME diet, respectively. SAMR1 mice were given LSO diet only until 50-weeks-old. The behavioral tests were performed at the timing of 49-weeks-old for 8 days. At the end of the experiment (50 weeks of age) following the behavioral analysis (open field test, Y-maze test, new object recognition test (NOR), and water-filled multiple T-maze) and the last day of the feeding, the mice were removed from their cages, decapitated and their brains carefully removed on ice. The whole brains were quickly frozen in liquid nitrogen in a sterile freeze tube and stored at -80ÂºC till extraction of total RNA followed by DNA microarray analysis using a whole-genome mouse chip (Agilent-014868, 4 x 44K (G4122F)) with two-color dye-swap approach in conjunction with IPA bioinformatic analysis. All animal studies were conducted in accordance with the Standards Relating to the Care Management of Experimental Animalsâ (Notice No. 6 of the Office of Prime Minister dated March 27, 1980) and with approval from the Animal Use Committee of Showa University (Approval Number: #04093).

Project description:Unravel the mechanisms underlying brain aging and Alzheimer´s disease (AD) has been difficult because of complexity of the networks that drive these aging-related changes. Analysis of the gene expression in the brain is a valuable tool to study the function of the brain under normal and pathological conditions. Gene microarray technology allows massively parallel analysis of most genes expressed in a tissue, and therefore is an important research tool that potentially can provide the investigative power needed to address the complexity of brain aging and neurodegenerative processes. One of the reasons that account for the resistance of AD pathogenesis to analysis is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging or AD. Here, we analyzed hippocampal and cortex frontal gene expression from 32 subjects separated in individuals presenting, 1) both pathologic and clinical AD (definitive AD); 2) AD pathology and normal clinic (pathologic AD); 3) cognitive impairment, without AD pathology (others dementias); and 4) no cognitive impairment, without AD pathology (normal individuals). Our results show that based on gene expression profile these individuals we could verify similarity between the definitive AD group and the group that only had AD-type pathology (pathologic AD). Specimens of hippocampus and cortex frontal used in this study were obtained at autopsy from 32 subjects. Neuropathology, specifically NFT and NP, was assessed in accordance to the Braak staging and CERAD scores, respectively. Based on pathologic and clinic criteria, subjects were categorized into four groups: 1) nine subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) presenting cognitive impairment (CDR ≥ 1), termed “definitive AD” (dAD); 2) five subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) and without cognitive impairment (CDR = 0), termed “pathologic AD” (pAD); 3) nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) presenting cognitive impairment (CDR ≥ 1), termed “other dementias” (OD); 4) - nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) and without cognitive impairment (CDR = 0), termed “normal” (N). RNA isolation and Amplification. From total RNA, a two-round linear amplification procedure (T7-based protocol) was carried out for all samples and for a pool of RNAs obtained from 15 distinct human cell lines used as reference. Labeled cDNA was generated in a reverse transcriptase reaction using amplified RNA (aRNA). Equal amounts of test and reference cDNA reverse color Cy-labeled aRNA targets were competitively hybridized against the cDNA probes in a customized cDNA platform with 4,608 ORESTES representing human genes. Dye-swap was performed for each sample as control for dye bias and used as replicate.

Project description:A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered an useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages in reference to age mated SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively, 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression towards a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer’s Disease (AD) and age-related cognitive impairment.

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Whole transcriptome analysis of brain hippocampal tissue from young and old senescence-accelerated prone SAMP8 mice treated with control diet and J147-containing diet

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