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 beta
amyloid production in an animal model of Alzheimer's
disease -- mice carrying mutations that are known to cause
inherited Alzheimer's disease in humans.
Since certain non-steroidal anti-inflammatory drugs
(NSAIDs) similarly reduce beta amyloid levels, but via a
slightly different mechanism, the researchers suggest that
combination therapy with lithium and NSAIDs could have an
enhanced effect in reducing amyloid peptide accumulation.
Lithium also protects neurons from stimuli that trigger
programmed neuronal cell death in Alzheimer's disease.
Pending development of new medications that target the
enzyme, the researchers suggest that lithium "might be
considered for the prevention of Alzheimer's disease,
especially in younger patients with an inherited form of
Alzheimer's disease or Down's syndrome."
The new findings have spurred interest in whether patients
taking lithium for bipolar disorder might have a lower
incidence of Alzheimer's disease, Klein noted.
Other participants in the study were: Drs. Christopher
Phiel, Christina Wilson, Virginia M.-Y. Lee., University of
Pennsylvania School of Medicine.
NIMH and NIA are part of the NIH, the Federal Government's
primary agency for biomedical and behavioral research. NIH
is a component of the U.S. Department of Health and Human
Services.
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