Multi-omic integration via similarity network fusion to detect molecular subtypes of ageing.

Molecular subtyping of brain tissue provides insights into the heterogeneity of common neurodegenerative conditions, such as Alzheimer's disease. However, existing subtyping studies have mostly focused on single data modalities and only those individuals with severe cognitive impairment. To address these gaps, we applied similarity network fusion, a method capable of integrating multiple high-dimensional multi-omic data modalities simultaneously, to an elderly sample spanning the full spectrum of cognitive ageing trajectories. We analyzed human frontal cortex brain samples characterized by five omic modalities: bulk RNA sequencing (18 629 genes), DNA methylation (53 932 CpG sites), histone acetylation (26 384 peaks), proteomics (7737 proteins) and metabolomics (654 metabolites). Similarity network fusion followed by spectral clustering was used for subtype detection, and subtype numbers were determined by Eigen-gap and rotation cost statistics. Normalized mutual information determined the relative contribution of each modality to the fused network. Subtypes were characterized by associations with 13 age-related neuropathologies and cognitive decline. Fusion of all five data modalities (n = 111) yielded two subtypes (n S1 = 53, n S2 = 58), which were nominally associated with diffuse amyloid plaques; however, this effect was not significant after correction for multiple testing. Histone acetylation (normalized mutual information = 0.38), DNA methylation (normalized mutual information = 0.18) and RNA abundance (normalized mutual information = 0.15) contributed most strongly to this network. Secondary analysis integrating only these three modalities in a larger subsample (n = 513) indicated support for both three- and five-subtype solutions, which had significant overlap, but showed varying degrees of internal stability and external validity. One subtype showed marked cognitive decline, which remained significant even after correcting for tests across both three- and five-subtype solutions (p Bonf = 5.9 × 10-3). Comparison to single-modality subtypes demonstrated that the three-modal subtypes were able to uniquely capture cognitive variability. Comprehensive sensitivity analyses explored influences of sample size and cluster number parameters. We identified highly integrative molecular subtypes of ageing derived from multiple high dimensional, multi-omic data modalities simultaneously. Fusing RNA abundance, DNA methylation, and histone acetylation measures generated subtypes that were associated with cognitive decline. This work highlights the potential value and challenges of multi-omic integration in unsupervised subtyping of post-mortem brain.

Functional Amyloids and their Possible Influence on Alzheimer Disease.

Amyloids play critical roles in human diseases but have increasingly been recognized to also exist naturally. Shared physicochemical characteristics of amyloids and of their smaller oligomeric building blocks offer the prospect of molecular interactions and crosstalk amongst these assemblies, including the propensity to mutually influence aggregation. A case in point might be the recent discovery of an interaction between the amyloid ß peptide (Aß) and somatostatin (SST). Whereas Aß is best known for its role in Alzheimer disease (AD) as the main constituent of amyloid plaques, SST is intermittently stored in amyloid-form in dense core granules before its regulated release into the synaptic cleft. This review was written to introduce to readers a large body of literature that surrounds these two peptides. After introducing general concepts and recent progress related to our understanding of amyloids and their aggregation, the review focuses separately on the biogenesis and interactions of Aß and SST, before attempting to assess the likelihood of encounters of the two peptides in the brain, and summarizing key observations linking SST to the pathobiology of AD. While the review focuses on Aß and SST, it is to be anticipated that crosstalk amongst functional and disease-associated amyloids will emerge as a general theme with much broader significance in the etiology of dementias and other amyloidosis.

Establishment of a cone photoreceptor transplantation platform based on a novel cone-GFP reporter mouse line.

We report successful retinal cone enrichment and transplantation using a novel cone-GFP reporter mouse line. Using the putative cone photoreceptor-enriched transcript Coiled-Coil Domain Containing 136 (Ccdc136) GFP-trapped allele, we monitored developmental reporter expression, facilitated the enrichment of cones, and evaluated transplanted GFP-labeled cones in wildtype and retinal degeneration mutant retinas. GFP reporter and endogenous Ccdc136 transcripts exhibit overlapping temporal and spatial expression patterns, both initiated in cone precursors of the embryonic retina and persisting to the adult stage in S and S/M opsin(+) cones as well as rod bipolar cells. The trapped allele does not affect cone function or survival in the adult mutant retina. When comparing the integration of GFP(+) embryonic cones and postnatal Nrl(-/-) 'cods' into retinas of adult wildtype and blind mice, both cell types integrated and exhibited a degree of morphological maturation that was dependent on donor age. These results demonstrate the amenability of the adult retina to cone transplantation using a novel transgenic resource that can advance therapeutic cone transplantation in models of age-related macular degeneration.

Divergent clonal selection dominates medulloblastoma at recurrence.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.