细胞期刊(Cell)2013-09-05 2:57 AM

Cell - Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease

Summary The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

细胞期刊(Cell)

0 Following 2 Fans 0 Projects 125 Articles

SIMILAR ARTICLES

Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To

Read More

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are gene

Read More

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are gene

Read More

Summary 5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring

Read More

Summary 5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring

Read More

Summary All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathog

Read More

Summary All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathog

Read More

Summary Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. I

Read More

Summary Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. I

Read More

Summary The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify

Read More