GSK-3—A Peripheral Marker for AD?

Different isoforms of glycogen synthase kinase-3 (GSK-3) have been linked to Alzheimer disease (AD). The β variant is one of several kinases that phosphorylate the microtubule-associated protein tau (see ARF related news story), which, when hyperphosphorylated, spurs formation of neurofibrillary tangles, one of the hallmarks of AD. The other hallmark of the disease, amyloid plaques, has been linked to GSK-3α, which is thought to increase production of amyloid-β (see ARF related news story). Might activity of the different forms of GSK-3, therefore, serve as a marker for progressing or even impending AD? In the January 3, 2005 issue of Neuroscience Letters (now available online), a paper by Simon Lovestone and colleagues at the Institute of Psychiatry, London, supports this idea.

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

Comments

  1. This paper adds an important molecule to the list of molecules found to be affected in peripheral cells in AD, and is consistent with a suggestion that AD is a systemic disease.

    View all comments by Paul Coleman

  2. Peripheral Diagnosis of Signaling Intermediates in Alzheimer Disease
    The need for accurate diagnostics in Alzheimer disease is one of the most pressing issues in the field today, and this is especially true for diagnostic tools, which employ easily attainable biological samples such as blood. Due to the apparent involvement of GSK-3 in both amyloid processing and tau phosphorylation as well as its expression in a number of diverse tissues, most notably, in this case circulating lymphocytes, GSK-3 is rapidly becoming a leading candidate as a diagnostic tool for Alzheimer disease. The finding of increased expression and activation of GSK-3 in MCI cases, but not in age-matched control cases, offers further support for the role of GSK-3 as a diagnostic tool for the early detection of Alzheimer disease (Hy et al., 2005). While this study focuses solely on the diagnostic potential of GSK-3 in Alzheimer disease, this same rationale also supports the diagnostic potential of other widely expressed cell signaling molecules known to play an early role in the pathogenesis of Alzheimer disease, including members of the MAPK pathway, such as ERK and JNK (Perry et al., 1999; Zhu et al., 2001a,b, 2004).

    Kate M. Webber, Mark A. Smith, Xiongwei Zhu, George Perry Institute of Pathology, Case Western Reserve University, Cleveland, Ohio

    References:

    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 Lett. 2005 Jan 3;373(1) PubMed.

    Perry G, Roder H, Nunomura A, Takeda A, Friedlich AL, Zhu X, Raina AK, Holbrook N, Siedlak SL, Harris PL, Smith MA. Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. Neuroreport. 1999 Aug 2;10(11):2411-5. PubMed.

    Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the 'two hit' hypothesis. Mech Ageing Dev. 2001 Dec;123(1):39-46. PubMed.

    Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, Smith MA. Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem. 2001 Jan;76(2):435-41. PubMed.

    Zhu X, Raina AK, Perry G, Smith MA. Alzheimer's disease: the two-hit hypothesis. Lancet Neurol. 2004 Apr;3(4):219-26. PubMed.

    View all comments by Kate Webber

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References

News Citations

  1. Wingless Pathway Helps Tauopathy Take Off
  2. Lithium Hinders Aβ Generation, Buffing Up GSK as Drug Target

Paper Citations

  1. Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004 Oct 12;63(7):1187-92. PubMed.
  2. Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci. 2004 Sep;25(9):471-80. PubMed.

Further Reading

Primary Papers

  1. 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 Lett. 2005 Jan 3;373(1) PubMed.

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