Upregulation of extracellular proteins in a mouse model of Alzheimer's disease

Various risk factors of Alzheimer's disease (AD) are known, such as advanced age, possession of certain genetic variants, accumulation of toxic amyloid-beta (A beta) peptides, and unhealthy lifestyle. An estimate of heritability of AD ranges from 0.13 to 0.25, indicating that its phenotypic variation is accounted for mostly by non-genetic factors. DNA methylation is regarded as an epigenetic mechanism that interfaces the genome with non-genetic factors. The Tg2576 mouse model has been insightful in AD research. These transgenic mice express a mutant form of human amyloid precursor protein linked to familial AD. At 9-13 months of age, these mice show elevated levels of A beta peptides and cognitive impairment. The current literature lacks integrative multiomics of the animal model. We applied transcriptomics and DNA methylomics to the same brain samples from similar to 11-month-old transgenic mice. We found that genes involved in extracellular matrix structures and functions are transcriptionally upregulated, and genes involved in extracellular protein secretion and localization are differentially methylated in the transgenic mice. Integrative analysis found enrichment of GO terms related to memory and synaptic functionability. Our results indicate a possibility of transcriptional modulation by DNA methylation underlying AD neuropathology.

Automated summary

Various risk factors, such as age, genetic variants, toxic amyloid-beta accumulation, and unhealthy lifestyle, contribute to the development of Alzheimer's disease. The heritability of AD is estimated to be between 0.13 and 0.25, indicating a significant contribution of non-genetic factors. DNA methylation, an epigenetic mechanism, plays a role in the interaction between the genome and these non-genetic factors. Using the Tg2576 mouse model, researchers found transcriptional upregulation of genes involved in extracellular matrix structures and functions, as well as differential methylation of genes involved in extracellular protein secretion and localization. The integrative analysis revealed enrichment of GO terms related to memory and synaptic functionability, suggesting a potential role of DNA methylation in AD neuropathology.