Perturbed sphingomyelin metabolism and accumulation of ceramides and cholesterol esters in Alzheimer's disease and ALS

Abstract

Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) involve selective degeneration of neurons involved in learning and memory (hippocampal and cortical neurons) and movement (spinal cord motor neurons), respectively. In each disorder and increase in oxidative stress is believed to render neurons vulnerable to excitotoxicity and apoptosis. We report abnormalities in sphingolipid and cholesterol metabolism in brain tissue of AD patients and a mouse model of AD (APP mutant mice), and in spinal cords of ALS patients and a transgenic mouse model of ALS (Cu/Zn‐SOD mutant mice), characterized by increased levels of sphingomyelin, long‐chain ceramides and cholesterol esters. In the mouse models these abnormalities precede the clinical phenotype. Exposure of cultured hippocampal neurons to amyloid β‐peptide (the neurotoxic component of amyloid plaques in AD) and of cultured motor neurons to oxidative insults, increases the accumulation of sphingomyelin, ceramides and cholesterol esters. Pharmacological inhibition of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol esters and protects hippocampal and motor neurons against death induced by insults relevant to AD and ALS. These findings suggest links between oxidative stress, altered sphingolipid and cholesterol metabolism and the pathogenesis of AD and ALS. Our data also identify novel targets for therapeutic intervention in neurodegenerative disorders.