Metabolic derangements mediate cognitive impairment and Alzheimer's disease: role of peripheral insulin-resistance diseases

Abstract

Herein, we review evidence that systemic insulin-resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Insulin-resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and endoplasmic reticulum (ER) stress. 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). These abnormalities establish or help propagate a cascade of neurodegeneration associated with increased ER stress and ceramide generation, which exacerbate brain insulin-resistance, cell death, myelin degeneration, and neuro-inflammation. The data suggest that a 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.

Figure 1

Extrinsic mechanisms of brain insulin/IGF resistance and neurodegeneration. In Type 2 diabetes, non-alcoholic steatohepatitis, and visceral obesity (visceral obesity shown as yellow discs below livers), excess lipid accumulation leads to insulin resistance, which promotes inflammation, ER stress, and oxidative injury. This process establishes a positive feedback cycle of mal-signaling and insulin resistance with impaired cell survival that results in leakage of toxic ceramides from liver (or visceral fat) to peripheral blood. Toxic ceramides capable of penetrating the blood brain barrier, cause CNS insulin resistance, oxidative stress, and pro-inflammatory cytokine activation, which ultimately result in dysregulated lipid metabolism, myelin breakdown, increased endogenous ceramide generation, and ER stress.