Unraveling the biological mechanisms in Alzheimer's disease — Lessons from genomics

Borovečki, Fran; Klepac, Nataša; Mück‐Šeler, Dorotea; Hajnšek, Sanja; Mubrin, Zdenko; Pivac, Nela

doi:10.1016/j.pnpbp.2010.12.019

Cited by 13 publications

(4 citation statements)

References 83 publications

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“…EOFAD presents before 65 years of age and there are multiple cases within a family usually attributable to mutations in the amyloid precursor protein ( APP ) gene, the presenilin ( PSEN)1 gene or the PSEN2 gene ( 33 ). By contrast, LOAD occurs after 65 years of age and is sporadic with no known single targetable cause ( 34 ). We would like to acknowledge that, due to ethical restrictions, we were unable to obtain more brain samples in order to investigate the expression and cellular distribution of other components of the mTOR signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

Elucidating the role of DEPTOR in Alzheimer’s disease

Davies

Zachariades

Rogers‐Broadway

et al. 2014

International Journal of Molecular Medicine

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The mammalian or mechanistic target of rapamycin (mTOR) is a Ser/Thr protein kinase that, in response to nutrient stimulation, regulates cellular growth, proliferation, survival, protein synthesis and gene transcription. It has also been implicated in Alzheimer’s disease (AD) with neuronal cells and hippocampal slices of AD transgenic mice experiencing dysregulated mTOR and synaptic plasticity in response to treatment with the toxic amyloid β (Aβ1–42) peptide, which has been implicated in AD. DEP domain-containing mTOR-interacting protein (DEPTOR) is a protein which can bind to mTOR and cause its inhibition, and functions as a regulatory protein of mTOR to control its activity. The inhibition of mTOR has been shown to have a neuroprotective effect; in an animal model, it was shown to protect against Aβ-induced neurotoxicity. In the present study, to investigate to role of DEPTOR in a model of AD, we neuronally differentiated the SH-SY5Y cell line and examined the effects of treatment with an Aβ42 peptide, thus mimicking plaque formation. This resulted in a significant increase in mTOR and a significant decrease in DEPTOR expression compared to the unstimulated controls. Moreover, to the best of our knowledge, we demonstrate for the first time a reduction in the protein level of DEPTOR in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with AD compared to a normal control, as well as a significant reduction in DEPTOR expression in samples from late-onset AD (LOAD) compared to early-onset familial AD (EOFAD). The reduction in DEPTOR expression in cases of AD compared to healthy controls can lead to an augmentation of mTOR signalling, leading to Aβ accumulation, which in turn leads to a further reduction in DEPTOR expression. This results in the accumulation of amyloid plaque, shifting the balance from neuroprotection to neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Elucidating the role of DEPTOR in Alzheimer’s disease

Davies

Zachariades

Rogers‐Broadway

et al. 2014

International Journal of Molecular Medicine

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“…Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. GWAS have yielded important new insights into the genetic mechanisms of AD [2]. However, newly identified AD susceptibility loci exert very small risk effects and cannot fully explain the underlying genetic risk [3].…”

Section: Introductionmentioning

confidence: 99%

Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

Zhang

Liao

et al. 2014

Mol Neurobiol

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Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. However, a large proportion of AD heritability has yet to be explained. We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in two AD GWAS. However, it is unclear whether CAM is present in the Genetic and Environmental Risk for Alzheimer's Disease Consortium (GERAD) GWAS and brain expression GWAS. Meanwhile, we think integrating AD GWAS and AD brain expression datasets may provide complementary information to identify important pathways involved in AD. Here, we conducted a systems analysis using (1) KEGG pathways, (2) large-scale AD GWAS from GERAD (n = 11,789), (3) two brain expression GWAS datasets (n = 399) from the AD cerebellum and temporal cortex, and (4) previous results from pathway analysis of AD GWAS. Our results indicate that (1) CAM is a consistent signal in five AD GWAS; (2) CAM is the most significant signal in AD; (3) we confirmed previous AD risk pathways related to immune system and diseases, and cardiovascular disease, etc.; and (4) we highlighted the purine metabolism pathway in AD for the first time. We believe that our results may advance our understanding of AD mechanisms and will be very informative for future genetic studies in AD.

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“…On the other hand, apolipoprotein E (APOE) is a well-known factor associated with both the development of CVD [ 48 , 49 , 50 ] and the development of AD [ 51 , 52 , 53 , 54 , 55 , 56 ]. However, there is little evidence of the involvement of this protein in the CVD/AD axis jointly [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Targets Linked to the Cardiovascular/Alzheimer’s Axis through Bioinformatics Approaches

et al. 2022

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The identification of common targets in Alzheimer’s disease (AD) and cardiovascular disease (CVD) in recent years makes the study of the CVD/AD axis a research topic of great interest. Besides aging, other links between CVD and AD have been described, suggesting the existence of common molecular mechanisms. Our study aimed to identify common targets in the CVD/AD axis. For this purpose, genomic data from calcified and healthy femoral artery samples were used to identify differentially expressed genes (DEGs), which were used to generate a protein–protein interaction network, where a module related to AD was identified. This module was enriched with the functionally closest proteins and analyzed using different centrality algorithms to determine the main targets in the CVD/AD axis. Validation was performed by proteomic and data mining analyses. The proteins identified with an important role in both pathologies were apolipoprotein E and haptoglobin as DEGs, with a fold change about +2 and −2, in calcified femoral artery vs healthy artery, respectively, and clusterin and alpha-2-macroglobulin as close interactors that matched in our proteomic analysis. However, further studies are needed to elucidate the specific role of these proteins, and to evaluate its function as biomarkers or therapeutic targets.

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Unraveling the biological mechanisms in Alzheimer's disease — Lessons from genomics

Cited by 13 publications

References 83 publications

Elucidating the role of DEPTOR in Alzheimer’s disease

Elucidating the role of DEPTOR in Alzheimer’s disease

Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

Identification of Potential Targets Linked to the Cardiovascular/Alzheimer’s Axis through Bioinformatics Approaches

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