Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed.

Ceramides are lipid signaling molecules that cause cytotoxicity and cell death mediated by insulin resistance, inflammation, and endoplasmic reticulum (ER) stress. However, insulin resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and ER stress. Herein, we discuss two major pathways, extrinsic and intrinsic, that converge and often overlap in propagating AD-type neurodegeneration via a triangulated mal-signaling network. First, we review evidence that systemic insulin resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues (e.g., liver) get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin resistance, inflammation, and cell death (extrinsic pathway). Then we discuss the role of the intrinsic pathway of neurodegeneration which is mediated by endogenous or primary brain insulin/IGF resistance, and impairs neuronal and oligodendrocyte survival, energy metabolism, membrane integrity, cytoskeletal function, and AβPP-Aβ secretion. The end result is increased ER stress and ceramide generation, which exacerbate brain insulin resistance, cell death, myelin degeneration, and neuroinflammation. Altogether, the data suggest that the triangulated mal-signaling network mediated by toxic ceramides, ER stress, and insulin resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade.