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Alternative poly(A) in Alzheimer's disase

ABSTRACT: Alternative polyadenylation (APA) contributes to post-transcriptional regulation, but its role in Alzheimer’s disease (AD) is largely unknown. Using high-resolution SQUARE multiple 3’ primer-based sequencing, we discovered massive APA differences in temporal gyrus tissues from demented AD patients compared to either healthy controls or non-demented donors with AD neuropathology (NDWP). Advanced statistics, microfluidics RT-PCR and protein measurements validated known and novel APA-modified 3’-intact transcripts. Moreover, APA modifications, more than total transcript counts, distinguished AD patients from both controls and NDWP donors and identified cell type-characteristic, cognition-associated and neuropathology-related changes. AD-enhanced APA variants included known therapeutic targets of brain, vascular and autoimmune disorders, predicting co-involvement of these target genes in AD progression; AD/NDWP increases in 3’-intact proteinopathy-related hnRNP mRNAs were inversely associated with protein decreases, whereas NDWP-potentiated cognition was accompanied by distinct ATP and mitochondrial variants. APA variations thus provide a novel resource of unique value for both basic and translational neuroscience researchers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57152 | GEO | 2017/04/27

SECONDARY ACCESSION(S): PRJNA245791

REPOSITORIES: GEO

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Project description:In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification which are likely induced by toxic beta-amyloid oligomers (dAbeta). To identify molecular targets downstream of dAbeta binding we prepared synaptoneurosomes from frontal cortex of control and IAD patients, and isolated mRNAs for comparison of gene expression. This approach elevated synaptic mRNAs above the threshold necessary for expression changes to be discriminated and also reduced other cellular mRNAs. In patients with minimal cognitive impairment (MCI) termed incipient AD (IAD) global measures of cognition declined with increasing levels of dimeric beta (dAbeta). These patients also showed increased expression of neuroplasticity related genes, many encoding 3' UTR consensus sequences that regulate local translation in the synapse. One such gene, GluR2, displayed elevated mRNA and protein expression in IAD. Other neurotransmitter-related genes were also upregulated. Overexpressed genes may induce compensatory as well as negative effects on cognition and provide targets for intervention to moderate the response to dAbeta. Experiment Overall Design: Patient information Experiment Overall Design: CNS tissues were obtained from the USC Alzheimer's Disease Research Center (ADRC) Neuropathology Core, NIA AG05142. Clinical information, including neurological examination, neuropsychological testing such as cognitive assessment, family history, and medications were provided by the USC ADRC Clinical Core. The groups did not differ significantly in age or years of education. Medication histories indicated one IAD patient had used a selective serotonin uptake inhibitor. Post-mortem interval (PMI) ranged from 2 to 9 hours (mean 5.1 hrs.). The study included 8 normal controls and 6 patients with Incipient Alzheimer's Disease. Experiment Overall Design: To augment studies comparing homogenates of control to AD brains, we used synaptoneurosome preparations to enrich for synaptic mRNAs. Synaptoneurosomes were prepared from the prefrontal cortices of control and IAD patients by a simple, rapid, but gentle method using sequential mesh screens.

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Alternative poly(A) in Alzheimer's disase

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