RAGE and DIAPH1 are increased in the human Medial Temporal Cortex in Alzheimer’s disease, however, Microglia RAGE may play a role in cognition in healthy adult mice

Identification: Derk, Julia


Description

RAGE and DIAPH1 are increased in the human Medial Temporal Cortex in Alzheimer's disease, however, Microglia RAGE may play a role in cognition in healthy adult mice
 
Julia Derk1, Keria Bermudez-Hernandez1, Meilun Hi1, Huilin Li1, Adam Mar1, Ann Marie Schmidt1*  
1New York University Medical School
*Corresponding Author
      
The Receptor for Advanced Glycation Endproducts (RAGE) is known to be expressed in a variety of cell types in the Central Nervous System (CNS) and the periphery, including: neurons, myeloid, epithelial, and endothelial cells. The principle consequences of ligand engagement of RAGE are to transduce inflammatory signaling via DIAPH1, including increased cytokine release, metabolic cellular shifts, migration alterations, and, in some cases, ignition of cell death cascades. Our current studies have illuminated that both RAGE and DIAPH1 are unregulated in myeloid cells in the human medial temporal cortex in the context of Alzheimer's disease, when compared to age-matched non-demented controls. In addition, this up regulation is strongly correlated to a decrease in ramified morphology and increase in lipid accumulation within myeloid cells. However, when we generated a novel mouse model in order to specifically delete RAGE from microglia in early or late AD-like syndrome in the APPSwe/PS1 mouse model, we were surprised to discover there were changes in specific behavioral domains in the non-demented microglia RAGE-deficient mice. Subsequently we have quantified microglia number, morphology, and phenotype in the hippocampus, cortex, and hypothalamus of our various mouse groups, and have found very specific alterations in both a RAGE and disease-state dependent manner. Thus, we conclude that RAGE may play an important homeostatic role in microglia, which is significantly altered by increased ligand burden in AD-like syndromes, but only in specific locations within the brain.
 

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