Phiel et al. discovered that lithium blocked the production of amyloid β-protein (Aβ) peptides by inhibiting glycogen synthase kinase 3α (GSK-3α) activity, opening the door to a new class of therapies for Alzheimer's disease. Amyloid plaques, which are primarily composed of Aβ40 and Aβ42 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 Aβ, a process that depends on the sequential proteolysis of amyloid precursor protein (APP). Lithium, which inhibits GSK-3α and GSK-3β, reduced secretion of Aβ40 and Aβ42 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 γ-secretase (which is involved in processing Notch as well as APP). Lithium did not affect Notch processing. Pharmacologic analysis, combined with manipulation of GSK-3α and GSK-3β levels through RNA interference and GSK-3α overexpression, indicated that lithium's inhibition of APP processing was mediated through GSK-3α. Therapeutic doses of lithium also reduced tissue levels of Aβ 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 γ-secretase cleavage of APP, these data suggest that GSK-3α 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-3α regulates production of Alzheimer's disease amyloid-β peptides. Nature 423, 435-439 (2003). [Online Journal]
B. De Strooper, J. Woodgett, Mental plaque removal. Nature 423, 392-393 (2003). [Online Journal]