Dataset Information

Integrative Functional Genomic Analysis of Molecular Signatures and Mechanistic Pathways in the Cell Cycle Underlying Alzheimer's Disease.

ABSTRACT:

Objective

Alzheimer's disease (AD) is associated with cell cycle reentry of mature neurons that subsequently undergo degeneration. This study is aimed to identify key regulators of the cell cycle and their underlying pathways for developing optimal treatment of AD.

Methods

RNA sequencing data were profiled to screen for differentially expressed genes in the cell cycle. Correlation of created modules with AD phenotype was computed by weight gene correlation network analysis (WGCNA). Signature genes for trophic factor receptors were determined using Pearson correlation coefficient (PCC) analysis.

Results

Among the 13,679 background genes, 775 cell cycle genes and 77 trophic factor receptors were differentially expressed in AD versus nondementia controls. Four coexpression modules were constructed by WGCNA, among which the turquoise module had the strongest correlation with AD. According to PCC analysis, 10 signature trophic receptors most strongly interacting with cell cycle genes were filtered and subsequently displayed in the global regulatory network. Further cross-talking pathways of signature receptors, such as glutamatergic synapse, long-term potentiation, PI3K-Akt, and MAPK signaling pathways, were identified.

Conclusions

Our findings highlighted the mechanistic pathways of signature trophic receptors in cell cycle perturbation underlying AD pathogenesis, thereby providing new molecular targets for therapeutic intervention in AD.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC8290224 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive.To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits.The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities.This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.