Organelle Stresses and Energetic metabolisms Promote Endothelial-to-Mesenchymal Transition and Fibrosis via upregulating FOSB and MEOX1 in Alzheimer's Disease

Fatma Saaoud¹Mohammed Ben Issa¹Lu Liu¹KEMAN XU¹Yifan Lu¹Ying Shao¹Baosheng Han¹Xiaohua Jiang¹Xiaolei Liu¹Avrum Gillespie¹Jin Jun Luo¹Laisel Martinez²Roberto Vazquez-Padron²Sadia Mohsin¹Beata Kosmider¹Hong Wang¹Silvia Fossati¹Xiaofeng Yang^1*

• ¹Temple University, Philadelphia, United States
• ²Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States

Transcriptomic changes associated with endothelial-to-mesenchymal transition (EndoMT), cell death, and fibrosis in Alzheimer's disease (AD) are not well understood. Using knowledge-based transcriptomic analysis, we found that in the 3xTg-AD model: i) multiple brain cell type genes are altered, promoting EndoMT through upregulation of RGCC and VCAN; ii) genes related to various types of cell death, including apoptosis, ferroptosis, necrosis, anoikis, mitochondrial outer membrane permeability programmed cell death, mitochondrial permeability transition-driven necrosis, NETotic, and mitotic cell death, are upregulated in the several brain cell types; iii) fibrosis-related genes are upregulated across multiple brain cell types. Further mechanistic analysis revealed: 1) mitochondrial stress through upregulation of mitochondrial genes in the brain cells; 2) upregulation of cellular, oxidative, and endoplasmic reticulum (ER) stress genes; 3) nuclear stress via upregulation of nuclear genes, transcription factors (TFs), and differentiation TFs FOSB and MEOX1; 4) metabolic reprogramming/stress through the upregulation of genes related to lipid and lipoprotein metabolism, fatty acid oxidation (FAO), glucose metabolism, and oxidative phosphorylation (OXPHOS); 5) catabolic stress via upregulation of catabolic genes. Single-cell RNA-Seq data indicated that many of these were also increased in AD patients' brain cells. These changes were reversed by knockdown of the ER stress kinase PERK (EIF2AK3) and deficiencies in FOSB and MEOX1. These findings provide novel insights into the roles of organelle stress and bioenergetic reprogramming in EndoMT, cell death, and fibrosis in AD brain pathology.