Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is extremely complex for both causal mechanism and clinical manifestation, requiring efforts to uncover its diversity and the corresponding mechanisms. Here, we applied a modelling analysis to investigate the regulation divergence among a large-scale cohort of AD patients. We found that transcription regulation tended to get degenerated in AD patients, which contributed to disease development and the detrimental clinical outcomes, mainly by disrupting protein degradation, neuroinflammation, mitochondrial and synaptic functions. To measure the accumulated effects, we came up with a new concept, regulation loss burden, which better correlated with AD related clinical manifestations and the ageing process. The epigenetic studies to multiple active regulation marks also supported a tendency of regulation loss in AD patients. Our finding can lead to a unified model as AD causal mechanism, where AD and its diversity are contributed by accumulated degeneration of transcriptional regulation.The significance of this study is that: (1) it is the first system biology investigation to transcription regulation divergence among AD patients; (2) we observed an accumulated degeneration of transcription regulation, which well correlates with detrimental clinical outcomes; (3) transcriptional degeneration also contributes to the ageing process, where its correlation with ages is up to 0.78. IntroductionAlzheimer's disease (AD) is a complex chronic neurodegenerative disease that has been intensively studied for decades. However, its causal mechanismd remain elusive [1]. More attentions have been focused on the visible neuropathological features, especially the amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed of depositions of insoluble and densely packed amyloid beta (A ) protein whereas neurofibrillary tangles are composed of aggregations of hyperphosphorylated tau protein [2]. Early-onset AD studies in rare families led to the discovery of three genes, amyloid precursor protein, presenilin 1, and presenilin 2 that demonstrated the causal effects of A in the AD progression [3]. However, this is challenged 1 by the observation that some patients with substantial accumulations of plaques have no cognitive impairment [4] and that drugs targeting A all failed in clinical studies [5]. Although neurofibrillary tangles have a stronger correlation with the decline of cognitive ability and have drawn more attentions recently [6,7], strong or direct evidence linking neurofibrillary tangles to AD is still lacking [8].Integrated systematic approaches, especially coexpression regulatory network analysis, have advanced our understanding of AD in different ways [9,10,11]. In such studies, biological networks are constructed using gene-expression data to identify the gene modules related to AD genesis and development by integrating quantitative evaluation into both AD neuropathology and cognitive ability decline. In our previous work, we studied transcriptional dysregulation between AD patients an...

Three-dimensional chromatin architecture datasets for aging and Alzheimer’s disease

“…The sorted and indexed bam files were merged together by samtools 43 into a single bam file, and then we performed peak calling using macs2 under a parameter setting of “–keep-dup all–broad–broad-cutoff 0.1”. ATAC-seq data were generated and analyzed as described in our previous work 28 , including the prefrontal cortex regions of 13 Chinese people with diagnosed with AD and 13 Chinese normal subjects. Like ChIP-seq data, AD and normal samples were merged for peak calling with a parameter setting of “–keep-dup all–nomodel–shift −100–extsize 200”.…”

“…For example, inhibition of the HDAC3 protein by RGFP966 can reverse AD-related pathologies in vitro and in vivo mouse models 27 . In our previous study using large-scale AD patients, we predicted that AD patients suffer from transcription regulation degeneration, which disrupts many AD-related pathways 28 . However, it is still not clear how the changes in the non-coding regulatory regions, especially epigenetic changes, contribute to AD genesis.…”