Linking lipids to Alzheimer's

A new study in the Proceedings of the National Academy of Sciences establishes a link between amyloid β-peptide (Aβ), oxidative stress and perturbed lipid metabolism in the pathogenesis of Alzheimer's disease (AD).

AD-associated neurodegeneration is thought to be facilitated by deposition of toxic Aβ and by oxidative stress. There is also indirect evidence for the involvement of altered lipid metabolism, so Mark Mattson and colleagues set out to investigate how these factors might interact.

Elevated levels of long-chain ceramides — lipid mediators that are generated in response to oxidative stress — and free cholesterol were detected post-mortem in the middle frontal gyrus of AD patients, a brain region that contained extensive Aβ plaques and neurofibrillary tangles. Adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were also present at high concentrations in this area. By contrast, the concentrations of ceramides, cholesterol and HNE adducts in the cerebellum, which contained few plaques and tangles, did not differ between AD patients and controls.

Is there a causal link between these indicators of abnormal lipid metabolism and the deposition of Aβ? To test this hypothesis, the authors exposed cultured rat hippocampal cells to Aβ_1–42. Within six hours, levels of long-chain ceramides, cholesterol and HNE had increased significantly. Similar results were obtained for neuronal cultures exposed to the oxidative agent iron, indicating that lipid peroxidation is sufficient to induce the changes associated with Aβ_1–42 treatment.

In the experiments described above, neuronal death occurred six to eighteen hours after altered lipid metabolism was first detected. Pretreatment of cultures with the antioxidant α-tocopherol prevented the Aβ_1–42-induced alterations of lipid levels and neuronal death. Incubation with an inhibitor of serine palmitoyltransferase to reduce ceramide levels also attenuated the proportion of neurons killed by Aβ_1–42. Taken together, these data indicate that Aβ causes oxidative stress, which alters ceramide and cholesterol metabolism and in turn leads to the degeneration of neurons. Inhibitors of enzymes involved in ceramide production, such as serine palmitoyltransferase and sphingomyelinase, might therefore offer protection against AD-associated neurodegeneration.