Ceramides may Play a Central Role in the Pathogenesis of Alzheimer's Disease: a Review of Evidence and Horizons for Discovery.

While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none have been entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders and psychological stress, contribute to this debilitating disease. Multiple lines of evidence indicate that ceramides may be central to the pathogenesis of Alzheimer's disease. Tumor necrosis factor-α, saturated fatty acids and cortisol elevate the brain levels of ceramides, while genetic risk factors, such as mutations in APP, presenilin, TREM2 and APOE ε4, also elevate ceramide synthesis. Importantly, ceramides displace sphingomyelin and cholesterol from lipid raft-like membrane patches that connect the endoplasmic reticulum and mitochondria, disturbing mitochondrial oxidative phosphorylation and energy production. As a consequence, the flattening of lipid rafts alters the function of γ-secretase, leading to increased production of Aβ₄₂. Moreover, ceramides inhibit the insulin-signaling cascade via at least three mechanisms, resulting in the activation of glycogen synthase kinase-3 β. Activation of this kinase has multiple consequences, as it further deteriorates insulin resistance, promotes the transcription of BACE1, causes hyperphosphorylation of tau and inhibits the transcription factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity and improves blood-brain barrier function. Thus, various seemingly unrelated Alzheimer's disease risk factors converge on ceramide production, whereas the elevated levels of ceramides give rise to the well-known pathological features of Alzheimer's disease. Understanding and targeting these mechanisms may provide a promising foundation for the development of novel preventive and therapeutic strategies.