Abstract
Alzheimer’s Disease (AD) is the most common cause of dementia affecting the elderly population worldwide. We have performed a comprehensive transcriptome profiling of Late-Onset AD (LOAD) patients using second generation sequencing technologies, identifying 2,064 genes, 47 lncRNAs and 4 miRNAs whose expression is specifically deregulated in the hippocampal region of LOAD patients. Moreover, analyzing the hippocampal, temporal and frontal regions from the same LOAD patients, we identify specific sets of deregulated miRNAs for each region, and we confirm that the miR-132/212 cluster is deregulated in each of these regions in LOAD patients, consistent with these miRNAs playing a role in AD pathogenesis. Notably, a luciferase assay indicates that miR-184 is able to target the 3’UTR NR4A2 - which is known to be involved in cognitive functions and long-term memory and whose expression levels are inversely correlated with those of miR-184 in the hippocampus. Finally, RNA editing analysis reveals a general RNA editing decrease in LOAD hippocampus, with 14 recoding sites significantly and differentially edited in 11 genes. Our data underline specific transcriptional changes in LOAD brain and provide an important source of information for understanding the molecular changes characterizing LOAD progression.
Highlights
Alzheimer’s Disease (AD) is the most common cause of dementia affecting the elderly population worldwide
ID assigned in the present study; ID: sample ID in the original Bank; Ctrl: Non-Demented Control; AD: Late-Onset AD (LOAD) Patient; PD: Parkinson’s Disease Patient; race: Ca = Caucasian; post-mortem interval (PMI): Post-Mortem Interval expressed in hours; Braak stage: index used to classify the degree of AD pathology; ND: Not defined; NICHD: Brain and Tissue
We used RNA-seq to examine the transcriptomic profile of the hippocampal CA1 region of a cohort of six patients affected by LOAD, six patients affected by PD and six cognitively normal controls (Table 1)
Summary
Alzheimer’s Disease (AD) is the most common cause of dementia affecting the elderly population worldwide. Pathological brain hallmarks are the presence of intraneuronal neurofibrillary tangles (NFTs) formed by twisted strands of hyperphosphorylated Tau, a microtubule-associated proteins (MAP), and of extracellular neuritic plaques containing β-Amyloid (Aβ) peptides, derived from proteolytic cleavage of the transmembrane glycoprotein Amyloid Precursor Protein (APP)[3] These neuropathological changes originate in the entorhinal cortex and hippocampal formations, spreading later into other temporal, parietal, and frontal association cortices[4,5]. We present a comprehensive transcriptome profiling study, utilizing RNA-seq technology, that has allowed the identification of specific changes in the expression profiles of coding and non-coding RNAs (miRNA and lncRNAs) and in RNA editing levels in the hippocampus of LOAD patients, compared to cognitively normal controls and patients affected by Parkinson’s Disease (PD) - as neurodegenerative disease controls. Our study sheds light on molecular mechanisms deregulated in the final stages of LOAD - identifying processes that could be valuable both in explaining the progression of the disease and in the rational design of therapeutic approaches
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