Dysfunctional Pro-Ceramide, ER Stress, and Insulin/IGF Signaling Networks with Progression of Alzheimer's Disease

Abstract

In Alzheimer’s disease (AD), brain insulin and insulin-like growth factor (IGF) resistance and deficiency begin early, and worsen with severity of disease. The factors mediating progression of brain insulin/IGF resistance in AD are not well understood. We hypothesize that AD progression is mediated via negative cross-talk that promotes toxic ceramide generation and endoplasmic reticulum (ER) stress. The rationale is that insulin resistance dysregulates lipid metabolism and promotes ceramide accumulation, and thereby increases inflammation and stress. Consequences include disruption of cytoskeletal function and AβPP-Aβ secretion. The present study correlates AD stage with activation of pro-ceramide genes, ceramide levels, and molecular indices of ER stress in postmortem human brain tissue. The results demonstrated that in AD, brain insulin/IGF resistance was associated with constitutive activation of multiple pro-ceramidegenes, increased ceramide levels, and increased expression of pro-ER stress pathway genes and proteins. Expression of several pro-ceramide and pro-apoptotic ER stress pathway molecules increased with AD severity and brain insulin/IGF resistance. In contrast, ER stress molecules that help maintain homeostasis with respect to unfolded protein responses were mainly upregulated in the intermediate rather than late stage of AD. These findings support our hypothesis that in AD, a triangulated mal-signaling network initiated by brain insulin/IGF resistance is propagated by the dysregulation of ceramide and ER stress homeostasis, which themselves promote insulin resistance. Therefore, once established, this reverberating loop must be targeted using multi-pronged approaches to disrupt the AD neurodegeneration cascade.

Brain metabolic dysfunction at the core of Alzheimer's disease

“…In fact, AD shares many features in common with systemic insulin resistance diseases including, reduced insulin-stimulated growth and survival signaling, increased oxidative stress, pro-inflammatory cytokine activation, mitochondrial dysfunction, and impaired energy metabolism [8,20,21]. In the early stages, AD is marked by deficits cerebral glucose utilization [22–24], and as AD progresses, brain metabolic derangements [25,26] with impairments in insulin signaling, insulin-responsive gene expression, glucose utilization, and metabolism worsen [18,19,27].…”

“…Furthermore, inflammation exacerbates insulin resistance and ceramide accumulation, i.e. lipotoxicity, and insulin resistance and lipotoxic injury and cell death worsen inflammation [50,67,68,21]. …”

“…Insulin/IGF resistance increases both oxidative and ER stress [21]. Persistent oxidative stress leads to reactive oxygen (ROS) and reactive nitrogen (RNS) species formation, as occur in AD [65].…”

“…ceramides, and activation of pro-inflammatory and pro-apoptosis cascades [7,84,85]. ER stress and dysregulated lipid metabolism in the brain worsen with severity of AD and brain insulin/IGF resistance [21]. Correspondingly, treatment with Liraglutide, a GLP-1 analogue, protects against high glucose-induced ER stress [86].…”

“…Yet, AD is clearly a metabolic degenerative disease with brain insulin/IGF resistance and deficiency. In addition, the brain-restricted insulin/IGF resistance is associated with dysregulated lipid metabolism, long-chain ceramide accumulation, inflammation, ER and oxidative stress, and mitochondrial dysfunction [21,142]. Although the causes of primary brain insulin/IGF resistance and deficiency in sporadic AD are not known, experimental evidence suggests roles for nitrosamine exposures.…”