Aging African Green Monkeys manifest transcriptional, pathological, and cognitive hallmarks of human Alzheimer’s disease
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE108282
PROVIDER: PRJNA423026 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6389670_1.fastq.gz | Fastqsanger.gz | |||
| SRR6389670_2.fastq.gz | Fastqsanger.gz | |||
| SRR6389680_1.fastq.gz | Fastqsanger.gz | |||
| SRR6389680_2.fastq.gz | Fastqsanger.gz | |||
| SRR6389690_1.fastq.gz | Fastqsanger.gz |
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Project description:While many preclinical models of Alzheimer’s disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in two higher order species, the African Green Monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and two AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments which improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.
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Project description:Investigation of whole genome gene expression level changes in African Green Monkeys treated with antimiR-33a/b, compared to the animal treated with vehicle The treatment of the monkeys is further described in Rottiers V, Obad S, McGarrah R, Black JC, Lindholm M, Goody R, Lawrence M, Whetstine JR, Gerszten RE, Kauppinen S, Näär AM. (2013). Pharmacological inhibition of a microRNA family in non-human primates by a seed-targeting 8-mer antimiR oligonucleotide. Accepted for publication at Science Translational Medicine. MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base-pairing with 3’ UTRs, primarily via seed sequences (nucleotides 2-8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequences and targets, but differ in the sequences outside of the seed. miRNAs have been implicated in the etiology of a wide variety of human diseases and therefore represent promising therapeutic targets. However, potential redundancy and compensatory action of different miRNAs sharing the same seed sequence, and the challenge of simultaneously targeting miRNAs that differ significantly in non-seed sequences complicates therapeutic targeting approaches. We recently demonstrated effective inhibition of entire miRNA families using seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiRs in short-term experiments in mammalian cells and in mice. However, the long-term efficacy and safety of this approach in higher organisms, such as humans and non-human primates, has not been determined. Here, we show that pharmacological inhibition of the miR-33 family, key regulators of cholesterol/lipid homeostasis, by a subcutaneously delivered 8-mer LNA-modified antimiR in obese and insulin-resistant non-human primates results in de-repression of miR-33 targets, such as ABCA1, increases circulating high-density lipoprotein-cholesterol (HDL-C), and is well tolerated over 108 days of treatment. These findings demonstrate the efficacy and safety of an 8-mer LNA-antimiR against a miRNA family in a non-human primate metabolic disease model, suggesting that this could be a feasible approach for therapeutic targeting of miRNA families sharing the same seed sequence in human diseases.
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