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Ceramide and Cholesterol: Possible Connections Between Normal Aging of the Brain and Alzheimer’s Disease
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In a paper just published in the inaugural issue of the new journal, Alzheimer's & Dementia, Claudio Costantini, Rekha Kolasani, and Luigi Puglielli argue that the lipids ceramide and cholesterol may provide metabolic links between AD and aging. There are numerous correlations between these lipids and aging and AD, they argue.
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As cells age, for example, ceramide levels rise in vivo, and the lipid is further increased by about threefold in the brains of AD patients. Through activation of ß-secretase, ceramide has also been implicated in production of amyloid-ß (Aß). A similar finger has been pointed at cholesterol, which has also been linked to AßPP processing through its impact on lipid rafts. Cholesterol may have more widespread effects, too, affecting isoprenoid biosynthesis, oxidative stress, and ozonolysis. Furthermore, many metabolic pathways may be shared by ceramide and cholesterol, further complicating interpretation of their specific roles in aging and disease.
See the background text below, the article by Costantini et al. (.pdf), and commentaries by Ann-Charlotte Granholm et al. (.pdf) and Gemma Casadesus et al. (.pdf) in the inaugural issue of Alzheimer's & Dementia. (Article and commentaries provided courtesy of Elsevier.)
Luigi Puglielli led this live discussion on 7 September 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
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 View Transcript of Live Discussion — Posted 15 October 2005
Background Text Even though it is known that aging is the single most important risk factor for Alzheimer disease (AD), there is a lack of information on the molecular pathway(s) that connect normal aging of the brain to this form of neuropathology. Because of the rise in average lifespan, the number of individuals that reach the seventh or eighth decade of life and become at high risk for AD is rapidly increasing. Current estimations predict that by 2050 about 45 to 50 million individuals will be affected by AD worldwide.
In this hypothesis paper that we were invited to write for the inaugural issue of Alzheimer's & Dementia, we discuss the need for age-directed research to understand age-associated disorders (in this case AD). Indeed, if we envision aging as a product of changes, we also need to accept the idea that molecular/biochemical pathways that are activated at a young age can become inactive at an old age. Conversely, pathways that are not active might become active. Therefore, the role of possible molecular targets, genetic polymorphisms, etc., should also be analyzed using aging paradigms.
In this paper, we also give a short overview of the possible role of cholesterol and ceramide as molecular connections between aging and AD, and as novel therapeutic targets for the prevention of late-onset AD. During the last few years, several groups (including ours) have identified new molecular events that link different aspects of cholesterol and ceramide metabolism to both the pathogenesis and progression of the Alzheimer form of neurodegeneration. Both lipids play important roles in brain functioning and are somehow affected by the normal process of aging. Obviously, it is now important to define their role in an age-dependent fashion and to identify the molecular/biochemical pathways that control their metabolism during the normal process of aging. This will ultimately help us design appropriate preventive strategies for AD.
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