ALZHEIMER'S DISEASE Lithium Inhibits Amyloid Production

Phiel et al. discovered that lithium blocked the production of amyloid ß-protein (Aß) peptides by inhibiting glycogen synthase kinase 3 (GSK-3) activity, opening the door to a new class of therapies for Alzheimer's disease. Amyloid plaques, which are primarily composed of Aß₄₀ and Aß₄₂ aggregates, and neurofibrillary tangles are two of the pathophysiological hallmarks of Alzheimer's disease. Phiel et al. investigated the possible involvement of GSK-3, which may contribute to the development of neurofibrillary tangles, in the production of Aß, a process that depends on the sequential proteolysis of amyloid precursor protein (APP). Lithium, which inhibits GSK-3 and GSK-3ß, reduced secretion of Aß₄₀ and Aß₄₂ from Chinese hamster ovary cells expressing APP without affecting steady-state levels of APP. Analysis of processing intermediates indicated that lithium inhibited APP processing at or before proteolysis by -secretase (which is involved in processing Notch as well as APP). Lithium did not affect Notch processing. Pharmacologic analysis, combined with manipulation of GSK-3 and GSK-3ß levels through RNA interference and GSK-3 overexpression, indicated that lithium's inhibition of APP processing was mediated through GSK-3. Therapeutic doses of lithium also reduced tissue levels of Aß in a mouse model of familial Alzheimer's disease. Because lithium inhibits the formation of both amyloid plaques and neurofibrillary tangles and apparently spares Notch processing, unlike other agents that affect -secretase cleavage of APP, these data suggest that GSK-3 inhibitors may have a role in the therapy of Alzheimer's disease. De Strooper and Woodgett discuss the background and implications of this research.

C. J. Phiel, C. A. Wilson, V. M.-Y. Lee, P. S. Klein, GSK-3 regulates production of Alzheimer's disease amyloid-ß peptides. Nature 423, 435-439 (2003). [Online Journal]

B. De Strooper, J. Woodgett, Mental plaque removal. Nature 423, 392-393 (2003). [Online Journal]