DIAPH1
Protein diaphanous homolog 1 (Diaphanous-related formin-1) (DRF1) [DIAP1]
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The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed. To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Animals
- Apolipoproteins E
- Case-Control Studies
- Claudin-1
- Female
- Formins
- Glial Fibrillary Acidic Protein
- Humans
- Imaging, Three-Dimensional
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Microscopy, Confocal
- Microtubule-Associated Proteins
- Myeloid Cells
- Receptor for Advanced Glycation End Products
- Temporal Lobe
- Up-Regulation
Keywords
- Alzheimer’s disease
- DIAPH1
- RAGE
- inflammation
- lipids
- microglia
- myeloid cells
This review focuses on the multi-ligand receptor of the immunoglobulin superfamily--receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging. In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand-RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; and tumors and Alzheimer's disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule--the formin DIAPH1. Physicochemical evidence of how the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences thereof, are also reviewed. We discuss the modalities of RAGE antagonism currently in preclinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain-DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging wherein RAGE ligands accumulate and signal.
MeSH Terms
- Aging
- Animals
- Chronic Disease
- Humans
- Ligands
- Receptor for Advanced Glycation End Products
- Signal Transduction
- Stress, Physiological
Keywords
- alzheimer’s disease
- diabetes
- inflammation
- neurodegeneration
- obesity
- receptor