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.

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach

“…In addition, an accumulation of Cer in the mitochondria increases the permeability of the outer mitochondrial membrane and stimulates the release of some pro-apoptotic proteins . This mitochondrial Cer accumulation has been previously observed in the pathogenesis of other diseases such as type 2 diabetes or Alzheimer’s disease . While it is not possible to confirm the accumulation of Cer in the mitochondria, given the changes observed in the pathogenesis of Long COVID, this approach aligns more closely with the observed results, Figure .…”

Metabolomic and proteomic applications to exercise biomedicine

“…Following 26 weeks of training, increases in PUFA and lysophospholipids, and decreases in ceramides, sphingolipids and phospholipids were observed. Ceramides and sphingolipids have previously been proposed as AD biomarkers and linked to cognitive function and mood regulation [ 31 , 32 ]. Thus, systemic metabolite markers that can assess the effects of exercise on AD-related outcomes offer potential for insights in disease progression, and development of therapeutics.…”

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

“…In the early stages of AD, there is an observed deficiency in multiple glucosides and elevated Cer in the lesion area ( Han et al, 2002 ). Lipidomics studies have revealed a threefold increase in ceramide levels in the brains of AD patients compared to healthy controls ( Chowdhury et al, 2022 ; Reveglia et al, 2023 ). Elevated plasma ceramide and sphingomyelin levels have also been found in AD patients and have been proposed as diagnostic markers for these diseases ( Olsen and Færgeman, 2017 ).…”