Dataset Information

Identification of prefrontal cortex protein alterations in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia in developed countries. A better understanding of the events taking place at the molecular level would help to identify novel protein alterations, which might be used in diagnosis or for treatment development. In this study, we have performed the high-throughput analysis of 706 molecules mostly implicated in cell-cell communication and cell signaling processes by using two antibody microarray platforms. We screened three AD pathological groups -each one containing four pooled samples- from Braak stages IV, V and VI, and three control groups from two healthy subjects, five frontotemporal and two vascular dementia patients onto Panorama and L-Series antibody microarrays to identify AD-specific alterations not common to other dementias. Forty altered proteins between control and AD groups were detected, and validated by i) meta-analysis of mRNA alterations, ii) WB, and iii) FISH and IHC using an AD-specific tissue microarray containing 44 samples from AD patients at different Braak stages, and frontotemporal and vascular dementia patients and healthy individuals as controls. We identified altered proteins in AD not common to other dementias like the E3 ubiquitin-protein ligase TOPORS, Layilin and MICB, and validated the association to AD of the previously controverted proteins DDIT3 and the E3 ubiquitin-protein ligase XIAP. These altered proteins constitute interesting targets for further immunological analyses using sera, plasma and CSF to identify AD blood- or cerebrospinal fluid-biomarkers and to perform functional analysis to determine their specific role in AD, and their usefulness as potential therapeutic targets of intervention.

SUBMITTER: Garranzo-Asensio M

PROVIDER: S-EPMC5834268 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Identification of prefrontal cortex protein alterations in Alzheimer's disease.

Garranzo-Asensio Maria M San Segundo-Acosta Pablo P Martínez-Useros Javier J Montero-Calle Ana A Fernández-Aceñero María Jesús MJ Häggmark-Månberg Anna A Pelaez-Garcia Alberto A Villalba Mayte M Rabano Alberto A Nilsson Peter P Barderas Rodrigo R

Oncotarget 20180124 13

Alzheimer's disease (AD) is the most common form of dementia in developed countries. A better understanding of the events taking place at the molecular level would help to identify novel protein alterations, which might be used in diagnosis or for treatment development. In this study, we have performed the high-throughput analysis of 706 molecules mostly implicated in cell-cell communication and cell signaling processes by using two antibody microarray platforms. We screened three AD pathologica ...[more]

PMID: 29541381

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Project description:Alzheimer's disease is a personally devastating neurodegenerative disorder and a major public health concern. There is an urgent need for medical imaging techniques that better characterize the early stages and monitor the progression of the disease. Magnetic resonance elastography (MRE) is a relatively new and highly sensitive MRI technique that can non-invasively assess tissue microstructural integrity via measurement of brain viscoelastic mechanical properties. For the first time, we use high-resolution MRE methods to conduct a voxel-wise MRE investigation and state-of-the-art post hoc region of interest analysis of the viscoelastic properties of the cerebral cortex in patients with Alzheimer's disease (N = 11) compared with cognitively healthy older adults (N = 12). We replicated previous findings that have reported significant volume and stiffness reductions at the whole-brain level. Significant reductions in volume were also observed in Alzheimer's disease when white matter, cortical grey matter and subcortical grey matter compartments were considered separately; lower stiffness was also observed in white matter and cortical grey matter, but not in subcortical grey matter. Voxel-based morphometry of both cortical and subcortical grey matter revealed localized reductions in volume due to Alzheimer's disease in the hippocampus, fusiform, middle, superior temporal gyri and precuneus. Similarly, voxel-based MRE identified lower stiffness in the middle and superior temporal gyri and precuneus, although the spatial distribution of these effects was not identical to the pattern of volume reduction. Notably, MRE additionally identified stiffness deficits in the operculum and precentral gyrus located within the frontal lobe; regions that did not undergo volume loss identified through voxel-based morphometry. Voxel-based-morphometry and voxel-based MRE results were confirmed by a complementary post hoc region-of-interest approach in native space where the viscoelastic changes remained significant even after statistically controlling for regional volumes. The pattern of reduction in cortical stiffness observed in Alzheimer's disease patients raises the possibility that MRE may provide unique insights regarding the neural mechanisms which underlie the development and progression of the disease. The measured mechanical property changes that we have observed warrant further exploration to investigate the diagnostic usefulness of MRE in cases of Alzheimer's disease and other dementias.

Project description:Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

Dataset Information

Identification of prefrontal cortex protein alterations in Alzheimer's disease.

Publications

Identification of prefrontal cortex protein alterations in Alzheimer's disease.

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