Next Article in Journal
GPCR-Hippo Signaling in Cancer
Next Article in Special Issue
pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo
Previous Article in Journal
Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma
Article Menu

Export Article

Open AccessArticle

Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development

1
Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK
2
Oxford Health NHS Foundation Trust, Oxford OX3 7JX, UK
3
GRIB, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain
4
Computational Sciences, Worldwide Research and Development, Pfizer Inc. 1 Portland St, Cambridge, MA 02139, USA
5
Neurosciences Therapeutic Area Unit, Glaxo Smith Kline R&D Ltd., Stevenage SG1 2NY, UK
6
Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8TA, UK
7
Members of the NIMA consortium, Cambridge, UK
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 425; https://doi.org/10.3390/cells8050425
Received: 8 April 2019 / Revised: 29 April 2019 / Accepted: 1 May 2019 / Published: 8 May 2019
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
  |  
PDF [1608 KB, uploaded 21 May 2019]
  |  

Abstract

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets. View Full-Text
Keywords: Alzheimer; JAK-STAT; multimodal; genomics; transcriptomics; animal models Alzheimer; JAK-STAT; multimodal; genomics; transcriptomics; animal models
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Nevado-Holgado, A.J.; Ribe, E.; Thei, L.; Furlong, L.; Mayer, M.-A.; Quan, J.; Richardson, J.C.; Cavanagh, J.; NIMA Consortium; Lovestone, S. Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development. Cells 2019, 8, 425.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top