An enzyme crucial to formation of Alzheimer's plaques and tangles may hold promise as a target for future medications, suggest studies in mice and cells. By blocking the enzyme, lithium stems the accumulation of beta amyloid, which forms Alzheimer's plaques, scientists funded by the National Institutes of Health (NIH) report in the May 22, 2003 Nature. Inhibiting the enzyme, glycogen synthase kinase 3 alpha (GSK-3 alpha), also blocks formation of neurofibrilary tangles by the tau protein.

"Although widely used to treat bipolar disorder, lithium's propensity to cause side-effects may limit its use in older people, who are more susceptible to Alzheimer's disease," cautioned Peter Klein, M.D., University of Pennsylvania School of Medicine, who led the research team, which was funded by the National Institute of Mental Health (NIMH) and the National Institute on Aging (NIA). It will also be important to develop "new agents" that specifically target GSK-3 alpha, he added.

To pinpoint the enzyme's role in the formation of amyloid plaques, the researchers first treated cells expressing the amyloid precursor protein with lithium, which they had earlier shown blocks GSK-3. Therapeutic doses of lithium inhibited the production of beta amyloid. Another GSK-3 inhibitor, structurally unrelated to lithium, also reduced production of beta amyloid, as did blocking expression of the GSK-3 alpha protein. Likewise, raising GSK-3 alpha levels enhanced beta amyloid production. These experiments established that the enzyme is required for maximal amyloid processing.

In mouse neurons expressing amyloid precursor protein, lithium significantly reduced production of beta amyloid. A therapeutic dose of lithium also markedly reduced the peptides and beta amyloid pro
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Contact: Jules Asher
NIMHpress@nih.gov
301-443-4536
NIH/National Institute of Mental Health
21-May-2003

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