Biology subjects

Ecca, F.

Publications and source records attributed to Ecca, F..

2 recordsLinked to original sources

bioRxiv2026

Pseudotime analysis of 2,106 brains across nine regions reveals conserved immune, neuronal, and myelin regulatory programs in Alzheimer's disease

Pseudotime trajectories can reconstruct latent disease progression from cross-sectional transcriptomic data. However, whether Alzheimer's disease (AD) progression follows a conserved molecular architecture across brain regions remains unclear. We applied pseudotime analysis to harmonized bulk RNA-seq data from 2,106 postmortem brain samples (1,364 AD, 742 controls) across nine brain regions from three AMP-AD cohorts (ROSMAP, Mayo, MSBB). Pseudotime was significantly associated with AD diagnosis in all nine regions and with Braak stage in seven of nine. We identified 21 genes with concordant pseudotime associations across all regions, increasing to 234 when the cerebellum was excluded. Pathway analysis revealed 1,268 significant associations, with synaptic deregulation as the most conserved process, and immune/ECM programs showing greater regional specificity. The cerebellum followed a distinct pattern, with enrichment for protein refolding and chaperone pathways rather than neurodegeneration. Co-expression network analysis identified six conserved metamodules, including immune/glial (MM1) and excitatory neuronal (MM2) programs spanning all nine regions, and an oligodendrocyte/myelin program (MM3) in seven cortical regions. Key driver analysis identified 76 unique genes across 35 modules, with HCK and LAPTM5 as the most broadly replicated immune regulators in seven regions. Oligodendrocyte-associated key drivers (MYRF, CNP, MOBP) increased along pseudotime in cortical regions, supporting active myelin remodeling during AD progression. These findings reveal a conserved transcriptional architecture underlying AD progression, organized around coordinated immune activation, synaptic loss, and myelin remodeling, with the cerebellum following a distinct trajectory.

neuroscience↗

bioRxiv2026

The TREM2-R47H Variant Drives Alzheimer's-Relevant Alterations in Forebrain Organoids Beyond Microglial Populations

Recent genetic studies highlight microglia as central drivers of Alzheimers disease (AD), yet how specific risk variants like TREM2-R47H influence broader neurocellular networks remains elusive. Here, we utilize an iPSC-derived forebrain organoid co-culture system to investigate the multi-lineage impact of the TREM2-R47H variant. High-resolution transcriptomic profiling, paired with confocal imaging, demonstrate that mutant organoids recapitulate AD-specific pathological signatures. Representative confocal imaging revealed phosphorylated-Tau (pTau) and amyloid-beta (A{beta}) internalization by WT microglia, while R47H variants showed a qualitative reduction in pTau accumulation. Single-cell RNA sequencing (scRNA-seq) revealed neurodegenerative transcriptional profiles in TREM2-R47H neurons as early as day 139, occurring independently of microglia presence. By day 173, these cell-intrinsic signatures intensified, characterized by disrupted oxidative phosphorylation and impaired maturation trajectories. Interaction analysis further demonstrated that the addition of microglia exacerbated this phenotype; while WT cells adapted to the microglia niche by activating homeostatic, neuro-supportive programs, TREM2-R47H cells underwent identity erosion and failed to transition into HLA-enriched activation states. This state was characterized by a failure to adopt brain-resident signatures and a divergent shift toward inflammatory myeloid phenotypes. These findings reveal that the TREM2-R47H mutation exerts a dual burden: it drives a baseline neurodegenerative state in neural lineages and renders them incapable of proper niche integration. Our study provides an in vitro human platform to dissect the interplay between genetic risk and multi-cellular dysfunction, establishing a scalable system for evaluating novel therapeutic interventions and drug screening aimed at restoring neuro-immune homeostasis in AD.

neuroscience↗