In the paper, lead author Dr Roy G Cutler (National Institutes of Health, Bethesda, MD) and colleagues explain that AD is characterized by the progression of A deposits and the degeneration of neurons in brain regions involved with learning and memory. While increased oxidative stress and neurotoxic forms of A are known to contribute to dysfunction and degeneration in AD, they suggest that alterations in lipid metabolism may be involved.

"Alterations in lipid metabolism may also play roles in AD because the risk of AD is affected by inheritance of different isoforms of apolipoprotein E, changes in cholesterol metabolism can affect A production in cell culture and in vivo, and drugs that lower cholesterol levels may reduce the risk of AD," write the authors.

One of the goals of the study was to investigate the accumulation of oxidatively damaged ceramides and cholesterol in a region of the brain vulnerable to AD. The authors explain that ceramides are the lipid component of glycosphingolipids and are mediators that are formed when enzymes activated by inflammatory cytokines and oxidative stress cleave the lipid sphingomyelin.

In seven autopsy-confirmed AD patients and seven age-matched controls, the authors measured levels of sphingomyelin, various ceramides, and cholesterol in tissue samples from two brain regions, one region vulnerable to AD and the other believed unaffected.

In the AD-vulnerable middle frontal gyrusa region of the brain with extensive A plaquesthere were significant increases in the levels of ceramide 24:0 and galactosylceramide, free cholesterol, and sphingomyelin. Levels of free cholesterol were also higher among AD patients with greater cognitive impairment than those with reported milder impairment, suggesting cholesterol accumulation is associated with cognitive deterioration.

The authors also obtained cortical tissue from male rats of three agesthree, six, and 25 monthsto study the possible association between lipids in brain cells and oxidative stress during normal aging.

Cutler and colleagues found that concentrations of ceramide in the cerebral cortex increased in an age-dependent manner, such that the concentration in 25-month-old mice was more than threefold greater than in three-month-old mice. There was also a significant age-dependent increase in the concentration of free cholesterol in cortical tissue samples. Markers of oxidative stress were also significantly higher in the cortical tissue of the 25-month-old mice compared with three- and six-month-old mice

In addition, the authors report that exposure of hippocampal neurons to A induces membrane oxidative stress and the accumulation of different ceramides and cholesterol. Treatment of the neurons with -tocopherol or an inhibitor of sphingomyelin synthesis protected against death induced by A, write the authors.

"Our findings suggest a sequence of events in the pathogenesis of AD in which A induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism, which, in turn, triggers a neurodegenerative cascade that leads to clinical disease," Cutler et al conclude.