Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

TLDR

Alzheimer’s disease is an age‑related neurodegenerative disorder marked by amyloid‑β deposition and neuronal loss, with oxidative stress implicated but the mechanisms linking these factors to cell death remaining unclear. We found that aging and AD brains accumulate long‑chain ceramides and cholesterol, and that amyloid‑β triggers membrane oxidative stress that drives this lipid dysregulation; antioxidant or sphingomyelin‑synthesis inhibition blocks lipid buildup and neuronal death, supporting a cascade from Aβ‑induced oxidative stress to lipid perturbation and neurodegeneration.

Abstract

Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid β-peptide (Aβ) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Aβ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Aβ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with α-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Aβ. Our findings suggest a sequence of events in the pathogenesis of AD in which Aβ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.