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Transcriptomic analysis of probable asymptomatic and symptomatic Alzheimer Brains

ABSTRACT: Objectives: Individuals with intact cognition and neuropathology consistent with Alzheimer’s disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Methods: Differential and co-expression analysis was performed on microarray profiled human brains of 27 control , 33 AsymAD and 52 AD subjects. Tissues known to be affected by AD neuropathology (entorhinal cortex, temporal cortex, frontal cortex) and tissue partially spared by the disease (cerebellum). Results: The AsymAD subjects exhibited significant changes in transcriptomic activity in the frontal cortex when compared to AD and control subjects. Fourteen genes (GPM6B, ANKEF1, NPC2, ALDH2, FBLN2, METTL7A, FLCN, ASPHD1, ARL5A, GPR162, HBA2, PCID2, BEND3 and RAP1Gap) were highly associated with AD neuropathology with overall disturbances in the “glutamate-glutamine cycle”, “oxidative phosphorylation”, “innate immune system”, “TYROBP network”, “neutrophil degranulation” and “amino acid metabolism” in both the AsymAD and AD subjects. Conclusions: Transcriptomic activity in AsymAD subjects suggests fundamental changes in AD brains may begin within the frontal cortex region. In addition, we provide new insight into the earliest biological changes occurring in the brain prior to clinical AD diagnosis which offers new avenues for therapeutic interventions for preventing AD. We provide access of gene-level results to the broader research community through a publicly available R SHINY web-application accessible at: https://phidatalab-shiny.rosalind.kcl.ac.uk/ADbrainDE

ORGANISM(S): Homo sapiens

PROVIDER: GSE118553 | GEO | 2019/07/22

REPOSITORIES: GEO

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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.

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Transcriptomic analysis of probable asymptomatic and symptomatic Alzheimer Brains

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