Protecting Brain Cells From Death Using Lipid Metabolic Drugs as a New Treatment for Alzheimer’s Disease

There is still no cure for Alzheimer’s disease (AD), therefore, a major challenge for researchers in the field is to develop new therapies that prevent or delay onset of this disease. During the AD process brain cells including neurons are under attack by high levels of the lipid ceramide. The consequence of this elevation is that neurons are not able to produce enough energy and are more easily programmed to die. Hence, in this research proposal, we propose to reduce ceramide levels in the brain to protect neurons from dying as a new therapy for AD.

A metabolic shift favoring ceramide formation in the brain has been proposed to play an important role in amyloid-β (Aβ) formation and neuronal death in Alzheimer’s disease (AD). However, how neurotoxicity is mediated and whether pharmacological inhibition of ceramide generation represents a valid approach to modify AD pathology is still uncertain. The long-term goal of this research proposal is to dissect mitochondria dysfunction mediated by ceramide in AD and identify specific targets that protect mitochondria homeostasis. Recently, it was demonstrated that ceramide synthases (CerS) and acid sphingomyelinase (A-SMase) play key roles in mediating mitochondria dysfunction. Our central hypothesis is that ceramide mediates neurotoxicity by affecting mitochondrial function in neurons and this process is prevented by inhibiting ceramide metabolic enzymes important for mitochondria homeostasis, such as CerS and A-SMase.