Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 2506 Gonda, 695 Charles E. Young Dr S, Los Angeles, CA 90095-1761, USA.
Archives of neurology (Impact Factor: 7.42). 10/2008; 65(10):1368-74. DOI: 10.1001/archneur.65.10.1368
Source: PubMed


Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found.
To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. Design, Setting, and
Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer's Genetics Study).
Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer's Genetics sample showed the same direction of association as the case-control sample.
To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.

Download full-text


Available from: George Jackson
  • Source
    • "In addition, GSK3 polymorphism has been linked to sporadic AD [82]. Finally, it is well accepted that tau is abnormally hyperphosphorylated in the AD brain [83] [84] leading to the formation of neurofibrillary tangles that are a well-documented hallmark of AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological evidence suggests that chronic treatment with simvastatin may protect against the development of Alzheimer's disease (AD), but as yet it is unclear how this effect is mediated. Extensive data also indicates that the amyloid β-protein (Aβ) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Aβ production or by counteracting the toxic effects of Aβ. Accordingly, using the AβPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Aβ-mediated toxicity. Since burgeoning data indicate that both fibrillar and non-fibrillar forms of Aβ play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Aβ. In untreated AβPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Aβ between 6 and 8 months, but this remained constant between 8 and 18 months. In contrast, the concentrations of detergent-soluble and formic acid (FA)-soluble Aβ species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Aβ remained relatively constant. LTP was normal at 6 months, but was significantly impaired at 8 and 18 months. Importantly, a diet supplemented with 0.04% simvastatin for one month (at 7 months) positively affected synaptic plasticity in AβPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Aβ, but did increase phosphorylation of both Akt and GSK-3, while tau and tau phosphorylation were unaltered. These results indicate that the protective effects of simvastatin may be mediated by maintaining signaling pathways that help to protect and rescue LTP.
    Full-text · Article · Oct 2013 · Journal of Alzheimer's disease: JAD
  • Source
    • "Importantly, many of the genes are involved in GSK3 signaling [44] [45]. Furthermore, GSK3 is directly related to the pathogenesis of AD as tau kinase [31]. Overall, it seems clear that GSK3 has an integral role in the pathogenesis of AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glycogen synthase kinase 3 (GSK3) has been implicated in neurological disorders; therefore, it is not surprising that there has been an increased focus towards developing therapies directed to this kinase. Unfortunately, these current therapies have not taken into consideration the physiological role of GSK3 in crucial events like synaptic plasticity. With this in mind we will discuss the relationship of synaptic plasticity with GSK3 and tau protein and their role as potential targets for the development of therapeutic strategies. Finally, we will provide perspectives in developing a cocktail therapy for Alzheimer's treatment.
    Full-text · Article · Jun 2012 · International Journal of Alzheimer's Disease
  • Source
    • "On the other hand, in nonfamilial dementia like sporadic Alzheimer disease, the presence of apolipoprotein E4 isoform could facilitate a higher GSK3 activity [19]. Also, a GSK3 polymorphism has been associated with Alzheimer's disease [20], and an increase in GSK3 activity has been suggested to take place in the brain of AD patients [21]. Finally, GSK3 phosphorylates the majority of sites, on tau molecule, which are abnormally phosphorylated in AD [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Almost a 20% of the residues of tau protein are phosphorylatable amino acids: serine, threonine, and tyrosine. In this paper we comment on the consequences for tau of being a phosphoprotein. We will focus on serine/threonine phosphorylation. It will be discussed that, depending on the modified residue in tau molecule, phosphorylation could be protective, in processes like hibernation, or toxic like in development of those diseases known as tauopathies, which are characterized by an hyperphosphorylation and aggregation of tau.
    Full-text · Article · May 2012 · International Journal of Alzheimer's Disease
Show more