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Alterations of the Sphingolipid Pathway in Alzheimer’s Disease: New Biomarkers and Treatment Targets?

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Abstract

The public health burden of Alzheimer disease (AD), the most common neurodegenerative disease, threatens to explode in the middle of this century. Current FDA-approved AD treatments (e.g. cholinesterase inhibitors, NMDA-receptor agonists) do not provide a “cure”, but rather a transient alleviation of symptoms for some individuals. Other available therapies are few and of limited effectiveness so additional avenues are needed. Sphingolipid metabolism is a dynamic process that modulates the formation of a number of bioactive metabolites, or second messengers critical in cellular signaling and apoptosis. In brain, the proper balance of sphingolipids is essential for normal neuronal function, as evidenced by a number of severe brain disorders that are the result of deficiencies in enzymes that control sphingolipid metabolism. Laboratory and animals studies suggest both direct and indirect mechanisms by which sphingolipids contribute to amyloid-beta production and Alzheimer pathogenesis but few studies have translated these findings to humans. Building on the laboratory and animal evidence demonstrating the importance of sphingolipid metabolism in AD, this review highlights relevant translational research incorporating and expanding basic findings to humans. A brief biological overview of sphingolipids (sphingomyelins, ceramides, and sulfatides) in AD is first described, followed by a review of human studies including post-mortem studies, clinical and epidemiological studies. Lastly, the potential role of peripheral ceramides in AD pathogenesis is discussed, as well as the possible use of sphingolipids as biomarkers for AD.

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Acknowledgments

This research was supported by grants from the National Institute on Aging (R21AG028754 and P50AG005146), the National Institute of Neurological Disorders and Stroke (R21NS060271-01) and a grant from the George and Cynthia Mitchell Fund.

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  1. Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Bayview, Alpha Commons Building, 4th floor, room 454, Baltimore, MD, 21224, USA

    Michelle M. Mielke & Constantine G. Lyketsos

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  1. Michelle M. Mielke
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  2. Constantine G. Lyketsos
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Correspondence to Michelle M. Mielke.

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Mielke, M.M., Lyketsos, C.G. Alterations of the Sphingolipid Pathway in Alzheimer’s Disease: New Biomarkers and Treatment Targets?. Neuromol Med 12, 331–340 (2010). https://doi.org/10.1007/s12017-010-8121-y

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  • DOI: https://doi.org/10.1007/s12017-010-8121-y

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