Add a new strand to the growing web of relationships among production of the Aβ peptide, regulation of cholesterol and other lipids, oxidative stress, and the death of neurons in Alzheimer's. Mark Mattson and colleagues at the National Institute on Aging in Baltimore, Maryland, believe that Aβ drives an increase in the conversion of sphingomyelin back into its precursor ceramide; this, in turn, increases cholesterol production, oxidative stress (resulting in more Aβ), and culminates in cell death. The researchers reported a series of experiments supporting this cycle of events last week at the annual meeting of the American Association for the Advancement of Science in Seattle, and published them February 17 in the early online edition of PNAS.
Ceramides, which can be produced de novo from serine and palmitoyl CoA, are short-lived intermediates in the production of sphingolipids such as the sphingomyelin component of membranes. Degradation of sphingomyelin is the other main source of ceramides. Though they are transient and not particularly abundant, these lipids are known to regulate various cellular processes ranging from developmental events to apoptosis, and they have been implicated in cell death in stroke and Parkinson's disease. Ceramides also help regulate cellular levels of cholesterol. Alzheimer's researchers have noted that ceramide is significantly increased in patients with mild cognitive impairment, leading to suggestions that this could be a biomarker for incipient AD (see consensus report from the Antecedent Biomarkers Group).
A putative role in Aβ generation has also been assigned to ceramides. Luigi Puglielli, working with Dora Kovacs at Massachusetts General Hospital in Charlestown, has found that increased ceramide levels stabilize and increase levels of BACE in vitro, with resultant increases in Aβ (see ARF related news story).
The new study by Mattson’s team explores changes in ceramide/sphingomyelin and cholesterol metabolism in animal and human tissues with an eye toward correlating these processes with both oxidative stress and Aβ-induced cell death. In an initial set of experiments, first author Roy Cutler and colleagues showed that in aging mice, ceramide and cholesterol levels increase, while sphingomyelin levels decrease, in an AD-vulnerable area (the middle frontal gyrus) but not in cerebellum. These changes correlated with increases in oxidative stress (as measured by increases in 4-hydoxynonenal adducts of lysine and histidines) in the middle frontal gyrus, but not in cerebellum.
In autopsy tissue from seven AD patients, the researchers detected similar changes. Ceramides and cholesterol, as well as oxidative stress, were increased in middle frontal gyrus but not cerebellum in AD patients versus controls. Sphingomyelin was decreased in middle temporal gyrus but not cerebellum. The researchers then examined brain tissue from four separate groups—AD patients with mild, moderate, or severe disease, and controls. This time looking only at membrane fractions from superior frontal cortex tissue, they found that increases in ceramides, and cholesterol, as well as oxidative stress correlated with the severity of disease.
The researchers then tested in cultured hippocampal neurons their hypothesis that Aβ deposition and the resulting oxidative stress could be responsible for these irregularities in lipid metabolism. They found that exposure to Aβ42 led to increases in ceramide, cholesterol, and cholesterol ester levels, along with decreases in sphingomyelin. Similarly, oxidative stress was increased in these neurons, which died within 24 hours of exposure to Aβ. Pretreating neurons with the antioxidant vitamin E reduced ceramide and cholesterol levels, and protected the neurons from Aβ-induced death. Similarly, pretreating the neurons to lower ceramide levels protected them from Aβ.
Mattson and colleagues have previously published evidence linking misregulation of sphingolipids to the death of cells in amyotrophic lateral sclerosis (Cutler et al., 2002), and just this month reported similar processes in HIV dementia (see Haughey et al., 2004). Based on their current findings, they propose a model whereby aging conspires with AD-specific genetic or environmental factors to increase Aβ production. Perturbed cholesterol and sphingolipid regulation, and oxidative stress, can both be causes and results of increased Aβ levels by this model. If this holds up in other studies, pharmacologic agents that affect sphingolipid metabolism could become therapeutic candidates, the authors suggest.—Hakon Heimer
Are you getting your fats mixed up? For advice on what's a ceramide, a sphingomyelin, and a glycosphingolipid, check out the Lipid Library.