Transcriptomic analysis of probable asymptomatic and symptomatic Alzheimer brains

TY - JOUR

T1 - Transcriptomic analysis of probable asymptomatic and symptomatic Alzheimer brains

AU - Patel, Hamel

AU - Hodges, Angela

AU - Curtis, Charles John

AU - Lee, Sang Hyuck

AU - Troakes, Claire

AU - Dobson, Richard James Butler

AU - Newhouse, Stephen

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Astrocytes

KW - Brain

KW - Frontal lobe

KW - Gene expression

KW - Gene regulatory networks

KW - Human

KW - Microarray analysis

KW - Mitochondria

KW - Neuropathology

UR - http://www.scopus.com/inward/record.url?scp=85065596053&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2019.05.009

DO - 10.1016/j.bbi.2019.05.009

M3 - Article

SN - 0889-1591

VL - 80

SP - 644

EP - 656

JO - Brain Behavior and Immunity

JF - Brain Behavior and Immunity

IS - 0

ER -