Transcriptomic analysis of probable asymptomatic and symptomatic alzheimer brains

Hamel Patel; Angela K Hodges; Charles Curtis; Sang Hyuck Lee; Claire Troakes; Richard J B Dobson; Stephen J Newhouse

doi:10.1016/j.bbi.2019.05.009

Transcriptomic analysis of probable asymptomatic and symptomatic alzheimer brains

Brain Behav Immun. 2019 Aug:80:644-656. doi: 10.1016/j.bbi.2019.05.009. Epub 2019 May 4.

Authors

Hamel Patel¹, Angela K Hodges², Charles Curtis³, Sang Hyuck Lee³, Claire Troakes⁴, Richard J B Dobson⁵, Stephen J Newhouse⁶

Affiliations

¹ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, UK.
² Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
³ NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, UK; Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, UK.
⁴ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK; London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
⁵ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, UK; Health Data Research UK London, University College London, 222 Euston Road, London, UK; Institute of Health Informatics, University College London, 222 Euston Road, London, UK; The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, 222 Euston Road, London, UK. Electronic address: richard.j.dobson@kcl.ac.uk.
⁶ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, UK; Health Data Research UK London, University College London, 222 Euston Road, London, UK; Institute of Health Informatics, University College London, 222 Euston Road, London, UK; The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, 222 Euston Road, London, UK. Electronic address: stephen.newhouse@kcl.ac.uk.

PMID: 31063847
DOI: 10.1016/j.bbi.2019.05.009

Abstract

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. Entorhinal cortex, frontal cortex, temporal cortex and cerebellum tissue from 27 control, 33 AsymAD and 52 AD human brains were microarray expression profiled. Differential expression analysis identified a significant increase of transcriptomic activity in the frontal cortex of AsymAD subjects, suggesting fundamental changes in AD may initially begin within the frontal cortex region prior to AD diagnosis. Co-expression analysis identified an overactivation of the brain "glutamate-glutamine cycle", and disturbances in the brain energy pathways in both AsymAD and AD subjects, while the connectivity of key hub genes in this network indicates a shift from an already increased cell proliferation in AsymAD subjects to stress response and removal of amyloidogenic proteins in AD subjects. This study provides new insight into the earliest biological changes occurring in the brain prior to the manifestation of clinical AD symptoms and provides new potential therapeutic targets for early disease intervention.

Keywords: Alzheimer’s disease; Astrocytes; Brain; Frontal lobe; Gene expression; Gene regulatory networks; Human; Microarray analysis; Mitochondria; Neuropathology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / genetics*
Alzheimer Disease / pathology*
Astrocytes / metabolism
Brain / metabolism
Cognition / physiology
Disease Progression
Female
Frontal Lobe / metabolism
Gene Expression / genetics
Gene Expression Profiling / methods
Gene Regulatory Networks / genetics*
Humans
Male
Mitochondria / genetics
Tissue Array Analysis / methods
Transcriptome / genetics

Abstract

Publication types

MeSH terms

Grants and funding