While many labs have focused on potential AD markers that might appear in the brain or cerebrospinal fluid (CSF), first author Abdul Hye and colleagues tried something different—they assayed GSK-3 in blood cells. When the authors measured both α and β variants in white cells, they found that the amount of protein was significantly higher in patients with AD (65 percent increase, n=60) or mild cognitive impairment (59 percent increase, n=33) versus levels in control samples (n=20). What’s more, the increases appear to reflect catalytically active protein, because levels of phosphorylated, inactive GSK-3 remained unchanged.

Why might white blood cell GSK-3 be related to AD? The authors suggest that insulin may be the key. GSK-3 is regulated by insulin signaling, and insulin has been linked to AD (see, for example, the recent paper by Luchsinger et al.). Whatever the reason, the findings suggest that measuring GSK-3 in circulating white blood cells may be useful in diagnosis of the disease, particularly as the protein was also found to be elevated in patients with mild cognitive impairment, which is often, but not always a forerunner of Alzheimer’s. However, the authors do stress that confirmation in larger and independent populations will be needed.

Because of the activities of the GSK-3 isoforms toward tau and Aβ production, they have also been eyed as a potential drug target for AD treatment. In fact, it was recently discovered that lithium, a well-known inhibitor of GSK-3α, attenuates Aβ formation (see ARF related news story). Lithium and more than 30 other GSK-3 inhibitors are reviewed by Paul Greengard and colleagues from The Rockefeller University, New York, in last September’s Trends in Pharmacological Sciences (see Meijer et al., 2004).—Tom Fagan.

Reference:
Hye A, Kerr F, Archer N, Foy C, Poppe M, Brown R, Hamilton G, Powell J, Anderton B, Lovestone S. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer’s disease. Neurosci. Letts. 2005 January;373:1-4. Abstract