Abstract
Alzheimer’s disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.
Highlights
The most common cause of dementia is late-onset Alzheimer’s disease (AD), which is associated with age > 65 years and leads to neuron death
Gene expression profiles were obtained from healthy-brain subjects and from AD-brain subjects (GSE5281) in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG)
Expressed protein interaction networks (PINs) in the other brain regions were significantly suppressed, regardless of the AD or normal-aging status of the brain. These results indicate that the EC region, one of the brain regions affected at the early stage in AD, was disrupted at the network level
Summary
The most common cause of dementia is late-onset Alzheimer’s disease (AD), which is associated with age > 65 years and leads to neuron death. Postmortem, the AD brain shows senile plaques on the surface of the cerebral neocortex and neurofibrillary tangle (NFT) staining. Senile plaques are deposits of amyloid beta protein (Aβ) spliced out by cleavage of the amyloid precursor protein (APP). NFTs are aggregations of aberrantly phosphorylated microtubule-associated protein tau (MAPT), a protein that lets microtubules stabilize in general. The deposit of NFTs expands from the central regions of the brain (e.g., entorhinal cortex, hippocampus) to the neocortex. This pathological stage of AD is defined by Braak stages. Braak stages are described as transentorhinal stages (Braak stages I‒II), limbic stages (Braak stages III‒IV) and isocortical stages (Braak stages V‒VI) [1]
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