Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, failure of neurotransmission, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and revealed many therapeutic possibilities. Among the mechanisms, sphingolipids are mentioned as distinctive mediators to be associated with the pathology of AD. Reportedly, alteration in the metabolism of sphingolipids and their metabolites result in the dysfunction of mitochondria, autophagy, amyloid beta regulation, and neuronal homeostasis, which exacerbates AD progression. Considering the importance of sphingolipids, in this review, we discuss the role of ceramide, a bioactive sphingolipid metabolite, in the progression and pathogenesis of AD. Herein, we describe the ceramide synthesis pathway and its involvement in the dysregulation of homeostasis, which eventually leads to AD. Furthermore, this review references different therapeutics proposed to modulate the ceramide pathway to maintain ceramide levels and prevent the disease progression.

Keywords: Alzheimer’s disease; amyloid beta; autophagy; ceramide; mitochondrial dysfunction; senescence.

Figure 1

Ceramide synthesis pathways; de novo synthesis, sphingomyelin hydrolysis and salvage pathway.

Figure 2

Mechanistic role of ceramide in the pathogenesis of AD.