A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early AD. The existence of a cell-autonomous mechanism linking AD pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in AD.

Joint embedding of biological networks for cross-species functional alignment.

MOTIVATION: Model organisms are widely used to better understand the molecular causes of human disease. While sequence similarity greatly aids this cross-species transfer, sequence similarity does not imply functional similarity, and thus, several current approaches incorporate protein-protein interactions to help map findings between species. Existing transfer methods either formulate the alignment problem as a matching problem which pits network features against known orthology, or more recently, as a joint embedding problem. RESULTS: We propose a novel state-of-the-art joint embedding solution: Embeddings to Network Alignment (ETNA). ETNA generates individual network embeddings based on network topological structure and then uses a Natural Language Processing-inspired cross-training approach to align the two embeddings using sequence-based orthologs. The final embedding preserves both within and between species gene functional relationships, and we demonstrate that it captures both pairwise and group functional relevance. In addition, ETNA's embeddings can be used to transfer genetic interactions across species and identify phenotypic alignments, laying the groundwork for potential opportunities for drug repurposing and translational studies. AVAILABILITY AND IMPLEMENTATION: https://github.com/ylaboratory/ETNA.

Application of Correlation Pre-Filtering Neural Network to DNA Methylation Data: Biological Aging Prediction.

We introduce the CPFNN (Correlation Pre-Filtering Neural Network) for biological age prediction based on blood DNA methylation data. The model is built on 20,000 top correlated DNA methylation features and trained by 1810 healthy samples from GEO database. The input data format and the instructions for parser and CPFNN model are detailed in this chapter. Followed by two potential uses, age acceleration detection and unknown age prediction are discussed.

Age Prediction by DNA Methylation in Neural Networks.

Aging is traditionally thought to be caused by complex and interacting factors such as DNA methylation. The traditional formula of DNA methylation aging is based on linear models and little work has explored the effectiveness of neural networks, which can learn non-linear relationships. DNA methylation data typically consists of hundreds of thousands of feature space and a much less number of biological samples. This leads to overfitting and a poor generalization of neural networks. We propose Correlation Pre-Filtered Neural Network (CPFNN) that uses Spearman Correlation to pre-filter the input features before feeding them into neural networks. We compare CPFNN with the statistical regressions (i.e., Horvath's and Hannum's formulas), the neural networks with LASSO regularization and elastic net regularization, and the Dropout Neural Networks. CPFNN outperforms these models by at least 1 year in term of Mean Absolute Error (MAE), with a MAE of 2.7 years. We also test for association between the epigenetic age with Schizophrenia and Down Syndrome ( p=0.024 and , respectively). We discover that for a large number of candidate features, such as genome-wide DNA methylation data, a key factor in improving prediction accuracy is to appropriately weight features that are highly correlated with the outcome of interest.