GSK-3 and memory formation

Abstract

In Alzheimer's disease (AD), tau hyperphosphorylation and neurofibrillary tangle (NFT) formation are strongly associated with dementia, a characteristic and early feature of this disease. Glycogen synthase kinase 3β (GSK-3β) is a pivotal kinase in both the normal and pathological phosphorylation of tau. In the diseased state, hyperphosphorylated tau is deposited in NFTs, the formation of which, drive the disease process. GSK-3β which is also involved in long-term depression induction, interacts with tau to inhibit synaptic long-term potentiation. Strong lines of evidence suggest that the activation of GSK-3β is responsible for the memory deficits seen in both advanced age and AD. In this review, we will focus on the role of GSK-3β in brain function, particularly in memory maintenance. We will examine human and mouse studies which suggest a role for GSK-3β in memory maintenance and the eventual development of memory deficits.

Full text

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MOLECULAR NEUROSCIENCE
MINI REVIEW ARTICLE
published: 23 April 2012
doi: 10.3389/fnmol.2012.00047
GSK-3β and memory formation
Akihiko Takashima*
Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi, Japan
Edited by:
Jim Robert Woodgett, Mount Sinai
Hospital, Canada
Reviewed by:
Oksana Kaidanovich-Beilin, Samuel
Lunenfeld Research Institute, Canada
Kenichi Okamoto, Samuel Lunenfeld
Research Institute of Mount Sinai
Hospital, Canada
*Correspondence:
Akihiko Takashima, Department of
Aging Neurobiology, Center for
Development of Advanced Medicine
for Dementia, National Center for
Geriatrics and Gerontology, 35 Gengo
Morioka, Obu-shi, Aichi 474-8511,
Japan. e-mail: kenneth@ncgg.go.jp
In Alzheimer’s disease (AD), tau hyperphosphorylation and neurofibrillary tangle (NFT) for-
mation are strongly associated with dementia, a characteristic and early feature of this
disease. Glycogen synthase kinase 3β (GSK-3β) is a pivotal kinase in both the normal
and pathological phosphorylation of tau. In the diseased state, hyperphosphorylated tau is
deposited in NFTs, the formation of which, drive the disease process. GSK-3β which is also
involved in long-term depression induction, interacts with tau to inhibit synaptic long-term
potentiation. Strong lines of evidence suggest that the activation of GSK-3β is responsible
for the memory deficits seen in both advanced age and AD. In this review, we will focus on
the role of GSK-3β in brain function, particularly in memory maintenance. We will examine
human and mouse studies which suggest a role for GSK-3β in memory maintenance and
the eventual development of memory deficits.
Keywords: Alzheimer’s disease, aging, memory formation, memory impairment, tau
ALZHEIMER’S DISEASE AND MEMORY
Memory impairment in old age is a hallmark of the initial stage
of Alzheimer’s disease (AD), with dementia developing in the
final stages (Poissonnet et al., 2012). AD is characterized by the
extensive deposition of amyloid β (Aβ), outside of neurons,
and the formation of neurofibrillary tangles (NFTs) consisting
of hyperphosphorylated tau, as intraneuronal inclusions (Selkoe,
1986). The relationship between the clinical course of AD and
the observed pathological changes is not yet fully understood.
Genetic studies of familial AD identified three causative genes,
APP, PSEN 1, and PSEN 2 (Tandon et al., 2000). Since these genes
form part of a cascade that results in Aβ generation, the Aβ hypoth-
esis emerged as a mechanism for AD pathophysiology (Hardy and
Selkoe, 2002). This theory states that Aβ deposition directly affects
neurons, inducing NFTs and neuronal death, leading to dementia.
Inheritance of the APP mutation leads to AD with 100% pene-
trance (Goate and Hardy, 2011). Mice engineered to overexpress
mutant human APP, show memory impairment along with Aβ
deposition (Gotz and Ittner, 2008), supporting the Aβ hypothe-
sis. Electrophysiological analyses indicate an inverse correlation
between Aβ levels and the amplitude of hippocampal long-term
potentiation (LTP; Walsh et al., 2002; Westerman et al., 2002), an
underlying mechanism of memory. A recent study found that
reducing tau alleviated Aβ-induced memory impairment in APP
transgenic (Tg) mice (Roberson et al., 2007), suggesting that tau
contributes to memory impairment in APP Tg mice. However,
contrary to these results, recent clinical trials show that reducing
Aβ generation, or removing Aβ deposits fail to halt the progression
of dementia (Holmes et al., 2008).
NFT FORMATION PROMOTES MEMORY IMPAIRMENT
AND DEMENTIA
The number of NFTs, unlike the extent of Aβ deposition, correlates
strongly with the degree of dementia (Gomez-Isla et al., 1997).
In diseased brains, synaptic and neuronal loss are prominent
in regions w ith detectable NFTs, implicating NFT formation in
AD associated memory impairment and dementia (Masliah et al.,
1992). Based on the observations of Braak and Braak (1990),as
AD progresses, NFTs are observed first in the entorhinal cortex,
a region integral to memory formation and maintenance, later
spreading into the limbic cortex and neocortex, regions asso-
ciated with emotions, and higher functioning such as thought,
respectively. Considering the role of these regions in normal brain
function, this sequential formation of NFTs could go some way
to explaining the clinical progression of AD. Before NFT for-
mation, tau is hyperphosphorylated by glycogen synthase kinase
3β (GSK-3β) activation and forms gr anular tau oligomers. This
hyperphosphorylated tau is associated with synapse loss (Kimura
et al., 2007), while granular tau oligomers are involved in neuronal
death. These data imply that the neuronal dysfunction resulting
from synaptic and neuronal loss (Kimura et al.,2010), occurs when
NFTs are formed.
NFT FORMATION PROMOTES NEURONAL DYSFUNCTION
Mice that overexpress P301L, a mutant form of tau, display age-
related NFTs, neuronal death, and memory deficits (Ramsden
et al., 2005; Santacruz et al., 2005). Although inhibiting mutant tau
overexpression in these mice blocks neuronal death and improves
memory, NFTs continue to form (Ramsden et al., 2005; Spires
et al., 2006). This suggests that NFTs in themselves are not toxic,
but instead, the processes of NFT for mation, neuronal death and
neuronal dysfunction underly the pathogenic mechanism.
The formation of tau fibrils follows three sequential steps
(Maeda et al., 2007; Kimura et al., 2008; Takashima, 2008), and
has been studied using atomic force microscopy (AFM). AFM
allows direct obser vation of tau aggregation in experimental solu-
tions, with no special pretreatments, in contrast to scanning
electron microscopy which requires several pretreatment steps.
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Takashima GSK-3β and memory formation
First, hyperphosphorylated monomeric tau binds together to form
soluble oligomers. The structure of these oligomers however, is
not discernible under AFM. Second, the soluble tau oligomers
takeonaβ-sheet structure, forming insoluble tau agg regates.
These aggregates become granular-shaped oligomers consisting
of approximately 40 tau molecules, which are detectable under
AFM. Third and finally, the increased concentration of granu-
lar tau causes these oligomers to fuse, forming tau fibrils (Maeda
et al., 2007).
As a major tau kinase, GSK-3β induces tau hyperphosphoryla-
tion, as one of the earliest events in NFT formation (Ishiguro et al.,
1988, 1993). Hyperphosphorylated tau or soluble tau oligomers
are associated with loss of synapses in wild type tau Tg mice
(Kimura et al., 2007), while granular tau oligomers are associated
with loss of neurons in P301L tau Tg mice (Kimura et al., 2010).
Thus, the intermediary, soluble and granular tau oligomers can
promote synaptic and neuronal loss before NFT formation. This
suggests that rather than being the cause of cell death, NFTs rep-
resent a biological tombstone, marking the sites of neuron death.
Therefore, memory impairment probably occurs when NFTs are
seen in the entorhinal cortex and hippocampus, since synaptic and
neuronal loss occur before the formation of NFTs in these regions.
TAU PHOSPHORYLATION BY GSK-3β
Tau protein kinase I (TPKI; Ishiguro et al., 1988), is encoded by
a nucleotide sequence identical to that of GSK-3β (Ishiguro
et al., 1993), but not GSK-3α. This kinase is activated by aggre-
gated Aβ and induces tau hyperphosphorylation as seen in NFTs
and neuron death, in hippocampal cultures (Takashima et al.,
1993, 1996). Phosphorylation of the tau Ser422 residue, a site
not phosphorylated by GSK-3β, is specifically seen in NFTs
(Morishima-Kawashima et al., 1995) indicating the involvement
of additional kinases in this process. While the Ser422 residue can
be phosphorylated by c-Jun amino-terminal kinase (JNK), this is
not enough to promote tau aggregation. In cultured cells at least,
both JNK and GSK-3β activation are needed to generate tau aggre-
gation (Sato et al., 2002). These results point to GSK-3β activation
as a requirement for AD pathogenesis.
Mice overexpressing GSK-3β show an accumulation of hyper-
phosphorylated tau, neuronal death in the hippocampus, and
memor y impairment in object recognition tests (Lucas et al., 2001;
Hernandez et al., 2002). These mice also exhibit reduced hip-
pocampal LTP (Hooper et al., 2007), and this memory deficit
is reversed when tau expression stops (de Barreda et al., 2010).
Reducing tau levels (Roberson et al., 2007) and inhibiting GSK-3
(Sereno et al., 2009) can each rescue memory impairment in APP
Tg mice. Aβ activates GSK-3β, inducing tau hyperphosphoryla-
tion in hippocampal neurons, and it is this GSK-3β activation that
leads to reduced LTP and eventual memory impairment in APP
Tg mice. Again, evidence shows that activation of GSK-3β isakey
factor in AD associated memory impairment, promoting the idea
that inhibitors of GSK-3β, may be potential therapeutic agents for
this disease.
GSK-3 INHIBITORS
Peineau et al. (2007) showed that GSK-3β localizes to postsynap-
tic regions and that GSK-3 inhibitors block NMDA-dependent
long-term depression (LTD) induction. Our own data (unpub-
lished) showsa blockade of LTD induction in GSK-3β heterozygote
knockout mice. Although several companies have developed GSK-
3 inhibitors, there are currently no successful candidates in Phase
III trials. Lithium, a longstanding therapeutic drug used in bipo-
lar disorder (Gould et al., 2006), is a specific inhibitor for GSK-3
(Klein and Melton, 1996). Lithium inhibits GSK-3 directly by com-
peting with mag nesium binding sites. It also acts indirectly, by
enhancing serine phosphorylation of GSK-3, as well as through
β-arrestin complex formation (reviewed in this Research Topic
series: Eldar-Finkelman and Martinez, 2011; Freland and Beaulieu,
2012). Lithium treatment inhibits tau hyperphosphorylation, and
NFT formation (Engel et al., 2006; Leroy et al., 2010), alleviating
memory deficits not only in mice overexpressing tau, but also mice
expressing both APP and PS1 (Zhang et al., 2011). Therefore hypo-
thetically, lithium inhibition of GSK-3β should halt the clinical
progression of AD in humans. While short-term lithium treatment
failed to improve cognitive function, a biomarker for AD (Hampel
et al., 2009), long-term treatment significantly reduced phospho-
rylated tau levels in cerebrospinal fluid, a potential biomarker for
AD, and improved cognitive function (Forlenza et al., 2011). Inter-
estingly, a retrospective study of bipolar and unipolar-depression
patients with a history of lithium treatment, found that these
patients had a higher risk of developing dementia (Dunn et al.,
2005). It therefore appears that GSK-3 performs a dual role.
In patients without dementia, GSK-3 activity maintains cogni-
tive function, whereas patients with dementia show excessive
activation of GSK-3.
THE ROLE OF GSK-3β IN SYNAPTIC PLASTICITY
GSK-3 exists as two isoforms, α and β, which share high sequence
identity and are encoded by genes on chromosomes 19 and 3
respectively, in humans (Woodgett, 1990). GSK-3β and GSK-
3α localize to different compartments. GSK-3β, but not GSK-3α
localizes to the mitochondria and synaptosomes (Hoshi et al.,
1995). Therefore it is likely that GSK-3β may be directly involved
in synaptic plasticity, while GSK-3α may act indirectly, via the
regulation of gene expression (more details in this Research Top-
ics series, as reviewed by Beaulieu et al., 2011; Polter and Li,
2011). These isoforms share common substrates including tau,
but they also have distinct functions. While knockout of GSK α
in mice induces increased insulin sensitivity, knockout of GSK-3β
in mice is embr yonically lethal (Hoeflich et al., 2000; MacAulay
et al., 2007).
GSK-3β is pivotal in the cascade leading to NFT formation,
which in turn drives dementia in AD. GSK-3β could be seen as a
time-delayed ignition switch in the brain, which in old age triggers
the process of dementia. As mentioned previously, patients with a
long history of lithium therapy, and consequentlysuppressed levels
of GSK-3, show a higher risk for developing dementia compared
with lithium naïve patients (Dunn et al., 2005). These observa-
tions imply that controlled levels of GSK-3 activity are required
for maintaining normal brain function, and as we already know,
excessive activation of GSK-3β, drives NFT formation, leading to
disease. Unraveling the dual role of GSK-3β requires an under-
standing of the physiological function of this protein in healthy
adult brains and how this changes with aging. As we know, GSK-3β
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Takashima GSK-3β and memory formation
FIGURE 1
|
Mechanism for memory formation and maintenance.
Learning stimulation leads to short-term memory, which lasts a few hours
and is converted to long-term memory through a process of consolidation.
Active memory is formed by recalling and updating long-term memory. This
updated memory becomes long-term memory through a process of
memory reconsolidation. Reconsolidation is a protein synthesis-dependent
process that is required for updating the reactivated memory and for
maintaining long-term memory.
is required for NMDA-dependent LTD induction (Peineau et al.,
2007). It is this requirement for GSK-3β in synaptic plasticity that
fuels the analysis of GSK-3β in memory formation.
GSK-3β ACTIVATION IS REQUIRED FOR MEMORY
RECONSOLIDATION
Learning stimuli first lead to short-term memory formation,
which lasts a few hours and is then converted to long-term
memory, through a process of memory consolidation. Active
memory is formed by recalling and updating long-term mem-
ory. This updated memory becomes long-term memory through
a process of memory reconsolidation. Reconsolidation is required
for updating reactivated memory, and maintaining long-term
memory (Figure 1). Although memory consolidation and recon-
solidation are thought to have distinct molecular pathways, both
are protein synthesis-dependent (Nader et al., 2000; Riccio et al.,
2002; Eisenberg et al., 2003; Biedenkapp and Rudy, 2004; Dudai
and Eisenberg, 2004; Lee et al., 2006; Morris et al., 2006). We used
GSK-3β heterozygous knockout mice (
+/−
) to understand how
GSK-3β fits into these pathways. While the homozygous GSK-3β
mutation is embryonically lethal, heterozygous mice express GSK-
3β at approximately 50%, and a relative activity was about 70%
of wild type mice (Kimura et al., 2008). For GSK-3α, the paralog
of GSK-3β, the total amount and relative activity of GSK-3α did
not differ between GSK-3β
+/−
and wild type mice. As previously
reported (Hoeflich et al., 2000), GSK-3β
+/−
mice are healthy and
fertile, with normal circadian rhythms, life span, and locomotor
activity, compared to w ild type mice.
In the contextual fear conditioning paradig m, GSK-3β
+/−
mice showed similar freezing times in response to unconditioned
stimuli as wild type mice, and there was no difference in the freeze
times between GSK-3β
+/−
and WT mice in the consolidation test
(Figure 2A; Kimura et al., 2008). This suggests no impairment in
the ability of GSK-3β
+/−
mice to form and consolidate memo-
ries, and that these memories can be maintained for at least 7 days,
the time period examined in this study (Kimura et al., 2008). In
reconsolidation however, GSK-3β
+/−
mice, showed significantly
less freeze time compared with wild type mice, at day 7 (Figure 2B;
Kimura et al., 2008). These results indicate that GSK-3β
FIGURE 2
|
(A) Deficiencies in GSK-3β do not affect the process of
memory consolidation. Mice were placed in a novel environment for 5 min
(CS) and then subjected to three sequential foot-shocks (US). On day 7
after conditioning, animals were placed in the original environment, without
shocks, for 5 min. The freezing time was recorded for these animals.
(B) Deficiencies in GSK-3
β impair memory reconsolidation. Mice were
placed in the environmental for 5 min (CS), and then subjected to three
sequential foot-shocks (US). One day after conditioning, animals were
exposed to the same environment for 5 min. Six days after their first
exposure to conditioning, animals were re-exposed again and the freezing
time was recorded.
heterozygotes are capable of learning and stabilizing long-term
memor y for 7 days, if memory is not reactivated. However, GSK-
3β
+/−
mice failed to achieve reconsolidation when memory was
reactivated once b efore testing (Kimura et al., 2008). The retro-
grade amnesia exhibited by these mice in the reconsolidation test of
contextual fear conditioning, points to possible impaired memory
reconsolidation, in keeping with the theory that GSK-3β activation
is required for memory reconsolidation or maintenance.
PROSPECTIVE ROLE OF GSK-3β IN BRAIN AGING
GSK-3β is involved in NMDA-dependent LTD induction and
memory reconsolidation (Peineau et al., 2007; also reviewed in
this Research Topic series by Bradley et al., 2012). However, the
relationship between LTD induction and memory reconsolida-
tion is unclear, although there are reports that LTD is important
for memory formation or new object recognition. Focusing on
synaptic plasticity, particularly LTP, genetic ablation of the NMDA
receptor impaired place learning in a LTD dependent manner
(Tsien e t al., 1996). Further analysis using CaMKIV knockout mice
indicates that late LTP is involved in the consolidation process of
memory formation (Kang et al., 2001). Thus, both LTP and LTD
contribute to memory formation, in which the memory consoli-
dation processes may preferentially depend on LTP, and memory
reconsolidation processes require LTD. In memory reconsolida-
tion, LTD maintains a prior potentiated circuit by competitive
synaptic maintenance (Diamond et al., 2005) and protects stable
memor y traces. This may explain why activation of GSK-3β is
required in reconsolidation but not in consolidation processes in
normal brain function. GSK-3β activation in the entorhinal cor-
tex and hippocampus is required for spatial recognition, in aged
but not young brains (unpublished result). While this process is
required for maintaining normal brain function in old age, the
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Takashima GSK-3β and memory formation
frequent activation of GSK-3β induces NFTs in the entorhinal cor-
tex (Braak and Braak, 1996) and hippocampus. It would therefore
appear that GSK-3β activation is an early e vent in normal brain
aging as well as AD.
We put forward that, generally, as we age, we learn and accu-
mulate many memories. When we are confronted with a new idea
or task, we draw on our experiences, that is, we recall related
memories to help us understand new information. The frequent
need to recall and reconsolidate memories relies on increased acti-
vation of GSK-3β and consequently, tau phosphorylation. Over
time, NFTs accumulate in the entorhinal cortex, which is a very
early pathological change in sporadic AD.
CONCLUSION
Tau hyperphosphorylation and NFT formation are early fea-
tures of dementia associated w ith AD. This major change in the
phosphor ylation state of tau leads to deposition of pathological
tau in NFTs, and these tangles are formed in a specific spatial and
temporal pattern within the brain. It is the for mation rather than
the presence of these NFTs that induces neuronal dysfunction and
death, leading to tauopathies.
GSK-3β is a major kinase for tau phosphorylation associated
with both physiological brain function and AD pathophysiol-
ogy. GSK-3β is also required for synaptic plasticity. Reduced
GSK-3 expression in GSK-3β
+/−
mice results in impaired mem-
ory reconsolidation emphasizing the importance of GSK-3 in
promoting memory maintenance via reconsolidation. A greater
understanding of how synaptic plasticity changes with aging,
through the analysis of AD-related molecules such as GSK-3β and
tau, would provide a solid platform of knowledge, from which
new therapeutic targets and innovative agents could be developed
for AD .
REFERENCES
Beaulieu, J. M., Del’Guidice, T., Sot-
nikova, T. D., Lemasson, M., and
Gainetdinov, R. R. (2011). Beyond
cAMP: the regulation of Akt and
GSK3 by dopamine receptors. Front.
Mol. Neurosci. 4:38. doi: 10.3389/
fnmol.2011.00038
Biedenkapp, J. C., and Rudy, J. W.
(2004). Context memories and reac-
tivation: constraints on the reconsol-
idation hypothesis. Behav. Neurosci.
118, 956–964.
Braak, H., and Braak, E. (1990). Neu-
rofibrillary changes confined to the
entorhinal region and an abundance
of cortical amyloid in cases of prese-
nile and senile dementia. Acta Neu-
ropathol. 80, 479–486.
Braak, H., and Braak, E. (1996).
Evolution of the neuropathology of
Alzheimer’s disease. Acta Neurol.
Scand. Suppl. 165, 3–12.
Bradley, C. A., Peineau, S., Taghibiglou,
C., Nicolas, C. S., Whitcomb, D. J.,
Bortolotto, Z. A., Kaang, B. K., Cho,
K., Wang, Y. T., and Collingridge,
G. L. (2012). A pivotal role of GSK-
3 in synaptic plasticity. Front. Mol.
Neurosci. 5:13. doi: 10.3389/fnmol.
2012.00013
de Barreda, E. G, Perez, M., Gomez
Ramos, P., De Cristobal, J., Martin-
Maestro, P., Moran, A., Dawson, H.
N., Vitek, M. P., Lucas, J. J., Her-
nandez, F., and Avila, J. (2010). Tau-
knockout mice show reduced GSK3-
induced hippocampal degeneration
and learning deficits. Neurobiol. Dis.
37, 622–629.
Diamond, D. M., Park, C. R., Camp-
bell, A. M., and Woodson, J.
C. (2005). Competitive interactions
between endogenous LTD and LTP
in the hippocampus underlie the
storage of emotional memories and
stress-induced amnesia. Hippocam-
pus 15, 1006–1025.
Dudai, Y., and Eisenberg, M. (2004).
Rites of passage of the engram: recon-
solidation and the lingering con-
solidation hypothesis. Neuron 44,
93–100.
Dunn, N., Holmes, C., and Mullee, M.
(2005). Does lithium therapy pro-
tect against the onset of dementia?
Alzheimer Dis. Assoc. Disord. 19,
20–22.
Eisenberg, M., Kobilo, T., Berman, D.
E., and Dudai, Y. (2003). Stability
of retrieved memory: inve rse corre-
lation with trace dominance. Science
301, 1102–1104.
Eldar-Finkelman, H., and Martinez, A.
(2011). GSK-3 inhibitors: preclini-
cal and clinical focus on CNS. Front.
Mol. Neurosci. 4:32. doi: 10.3389/
fnmol.2011.00032
Engel, T., Goni-Oliver, P., Lucas, J. J.,
Avila, J., and Hernandez, F. (2006).
Chronic lithium administration to
FTDP-17 tau and GSK-3beta over-
expressing mice prevents tau hyper-
phosphorylation and neurofibrillary
tangle formation, but pre-formed
neurofibrillary tangles do not revert.
J. Neurochem. 99, 1445–1455.
Forlenza, O. V., Diniz, B. S., Radanovic,
M., Santos, F. S., Talib, L. L., and Gat-
taz, W. F. (2011). Disease-modifying
properties of long-term lithium treat-
ment for amnestic mild cognitive
impairment: randomised controlled
trial. Br. J. Psychiatry 198, 351–356.
Freland, L., and Beaulieu, J. M. (2012).
Inhibition of GSK3 by lithium, from
single molecules to signaling net-
works. Front. Mol. Neurosci. 5:14. doi:
10.3389/fnmol.2012.00014
Goate, A., and Hardy, J. (2011). Twenty
years of Alzheimer’s disease-causing
mutations. J. Neurochem. Suppl. 1,
3–8.
Gomez-Isla, T., Hollister, R., West, H.,
Mui, S., Growdon, J. H., Petersen, R.
C., Parisi, J. E., and Hyman, B. T.
(1997). Neuronal loss correlates with
but exceeds neurofibrillary tangles in
Alzheimer’s disease. Ann. Neurol. 41,
17–24.
Gotz, J., and Ittner,L. M. (2008). Animal
models of Alzheimer’s disease and
frontotemporal dementia. Nat. Rev.
Neurosci. 9, 532–544.
Gould, T. D., Picchini, A. M., Einat,
H., and Manji, H. K. (2006). Tar-
geting glycogen synthase kinase-3 in
the CNS: implications for the devel-
opment of new treatments for mood
disorders. Curr. Drug Targets 7,
1399–1409.
Hampel, H., Ewers, M., Burger, K.,
Annas, P., Mortberg, A., Bogst-
edt, A., Frolich, L., Schroder, J.,
Schonknecht, P., Riepe, M. W., Kraft,
I., Gasser, T., Leyhe, T., Moller, H.
J., Kurz, A., and Basun, H. (2009).
Lithium trial in Alzheimer’s disease:
a randomized, single-blind, placebo-
controlled, multicenter 10-week
study. J. Clin. Psychiatry 70, 922–931.
Hardy, J., and Selkoe, D. J. (2002). The
amyloid hypothesis of Alzheimer’s
disease: progress and problems on
the road to therapeutics. Science 297,
353–356.
Hernandez, F., Borrell, J., Guaza, C.,
Avila, J., and Lucas, J. J. (2002).
Spatial learning deficit in transgenic
mice that conditionally over-express
GSK-3beta in the br ain but do not
form tau filaments. J. Neurochem. 83,
1529–1533.
Hoeflich, K. P., Luo, J., Rubie, E. A.,
Tsao, M. S., Jin, O., and Woodgett, J.
R. (2000). Requirement for glycogen
synthase kinase-3beta in cell sur vival
and NF-kappaB activation. Nature
406, 86–90.
Holmes, C., Boche, D., Wilkinson, D.,
Yadegarfar, G., Hopkins, V., Bayer, A.,
Jones, R. W., Bullock, R., Love, S.,
Neal, J. W., Zotova, E., and Nicoll, J. A.
(2008). Long-term effects of Abeta42
immunisation in Alzheimer’s disease:
follow-up of a randomised, placebo-
controlled phase I trial. Lancet 372,
216–223.
Hooper, C., Markevich, V., Plattner, F.,
Killick, R., Schofield, E., Engel, T.,
Hernandez, F., Anderton, B., Rosen-
blum, K., Bliss, T., Cooke, S. F., Avila,
J., Lucas, J. J., Giese, K. P., Stephenson,
J., and Lovestone, S. (2007). Glycogen
synthase kinase-3 inhibition is inte-
gral to long-term potentiation. Eur. J.
Neurosci. 25, 81–86.
Hoshi, M., Sato, M., Kondo, S.,
Takashima, A., Noguchi, K., Taka-
hashi, M., Ishiguro, K., and Imahori,
K. (1995). Different localization of
tau protein kinase I/glycogen syn-
thase kinase-3 beta from glycogen
synthase kinase-3 alpha in cerebel-
lum mitochondria. J. Biochem. 118,
683–685.
Ishiguro, K., Ihara, Y., Uchida, T., and
Imahori, K. (1988). A novel tubulin-
dependent protein kinase forming a
paired helical filament epitopeon tau.
J. Biochem. 104, 319–321.
Ishiguro, K., Shiratsuchi, A., Sato, S.,
Omori, A., Arioka, M., Kobayashi,
S., Uchida, T., and Imahori, K.
(1993). Glycogen synthase kinase 3
beta is identical to tau protein kinase
I generating several epitopes of paired
helical filaments. FEBS Lett. 325,
167–172.
Kang, H., Sun, L. D., Atkins, C. M.,
Soderling, T. R., Wilson, M. A.,
and Tonegawa, S. (2001). An impor-
tant role of neural activity-dependent
CaMKIV signaling in the consolida-
tion of long-term memory. Cell 106,
771–783.
Kimura, T., Fukuda, T., S ahara,
N., Yamashita, S., Murayama, M.,
Mizoroki, T., Yoshiike, Y., Lee, B.,
Sotiropoulos, I., Maeda, S., and
Takashima, A. (2010). Aggregation of
detergent-insoluble tau is involved in
Frontiers in Molecular Neuroscience www.frontiersin.org April 2012
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“fnmol-05-00047” — 2012/4/21 — 12:59 — page5—#5
Takashima GSK-3β and memory formation
neuronal loss but not in synaptic loss.
J. Biol. Chem. 285, 38692–38699.
Kimura, T., Yamashita, S., Fukuda, T.,
Park, J. M., Murayama, M., Mizoroki,
T., Yoshiike, Y., Sahara, N., and
Takashima, A. (2007). Hyperphos-
phorylated tau in parahippocampal
cortex impairs place learning in aged
mice expressing wild-type human
tau. EMBO J. 26, 5143–5152.
Kimura, T., Yamashita, S., Nakao, S.,
Park, J. M., Murayama, M., Mizoroki,
T., Yoshiike, Y., Sahara, N., and
Takashima, A. (2008). GSK-3β is
required for memory reconsolidation
in adult brain. PLoS ONE 3, e3540.
doi: 10.1371/jour nal.pone.0003540
Klein, P. S., and Melton, D. A.
(1996). A molecular mechanism for
the effect of lithium on development.
Proc. Natl. Acad. Sci. U.S.A. 93,
8455–8459.
Lee, J. L. C., Milton, A. L., and Everitt,
B. J. (2006). Reconsolidation and
extinction of conditioned fear: inhi-
bition and potentiation. J. Neurosci.
26, 10051–10056.
Leroy, K., Ando, K., Heraud, C., Yil-
maz, Z., Authelet, M., Boeynaems,
J. M., Buee, L., De Decker, R., and
Brion, J. P. (2010). Lithium treatment
arrests the development of neurofib-
rillary tangles in mutant tau trans-
genic mice with advanced neurofib-
rillary pathology. J. Alzheimers Dis.
19, 705–719.
Lucas, J. J., Hernandez, F., Gomez-
Ramos, P., Moran, M. A., Hen,
R., and Avila, J. (2001). Decreased
nuclear beta-catenin, tau hyperphos-
phorylation and neurodegeneration
in GSK-3beta conditional transgenic
mice. EMBO J. 20, 27–39.
MacAulay, K., Doble, B. W., Patel, S.,
Hansotia, T., Sinclair, E. M., Drucker,
D. J., Nagy, A., and Woodgett, J.
R. (2007). Glycogen synthase kinase
3alpha-specific regulation of murine
hepatic glycogen metabolism. Cell
Metab. 6, 329–337.
Maeda, S., Sahara, N., Saito, Y.,
Murayama, M., Yoshiike, Y., Kim,
H., Miyasaka, T., Murayama, S., Ikai,
A., and Takashima, A. (2007). Gran-
ular tau oligomers as intermediates
of tau filaments. Biochemistry 46,
3856–3861.
Masliah, E., Ellisman, M., Carragher,
B., Mallory, M., Young, S., Hansen,
L., Deteresa, R., and Terry, R. D.
(1992). Three-dimensional analysis
of the relationship between synap-
tic pathology and neuropil threads
in Alzheimer disease. J. Neuropathol.
Exp. Neurol. 51, 404–414.
Morishima-Kawashima, M., Hasegawa,
M., Takio, K., Suzuki, M., Yoshida,
H., Titani, K., and Ihara, Y. (1995).
Proline-directed and non-proline-
directed phosphorylation of PHF-
tau. J. Biol. Chem. 270, 823–829.
Morris, R. G. M., Inglis, J., Ainge, J. A.,
Olverman, H. J., Tulloch, J., Dudai,
Y., and Kelly, P. A. T. (2006). Memory
reconsolidation: sensitivity of spatial
memory to inhibition of protein syn-
thesis in dorsal hippocampus during
encoding and retrieval. Neuron 50,
479–489.
Nader, K., Schafe, G. E., and Ledoux, J.
E. (2000). The labile nature of con-
solidation theor y. Nat. Rev. Neurosc i.
1, 216–219.
Peineau, S., Taghibiglou, C., Bradley, C.,
Wong, T. P., Liu, L., Lu, J., Lo, E., Wu,
D., Saule, E., Bouschet, T., Matthews,
P., Isaac, J. T., Bortolotto, Z. A., Wang,
Y. T., and Collingridge, G. L. (2007).
LTP inhibits LTD in the hippocampus
via regulation of GSK3beta. Neuron
53, 703–717.
Poissonnet, A., Henry-Feugeas, M. C.,
Drunat, O., Wolmark, Y., Delpierre,
S., and Koskas, P. (2012). Evaluation
of visual recognition memory for the
early diagnosis of Alzheimer’s disease
in patients over 75 years. Rev. Neu-
rol. doi: 10.1016/j.neurol.2011.11.004
[Epub ahead of print].
Polter, A. M., and Li, X. (2011).
Glycogen synthase kinase-3 is an
intermediate modulator of sero-
tonin neurotransmission. Front. Mol.
Neurosci. 4:31. doi: 10.3389/fnmol.
2011.00031
Ramsden, M., Kotilinek, L., Forster, C.,
Paulson, J., Mcgowan, E., Santacruz,
K., Guimaraes, A., Yue, M., Lewis, J.,
Carlson, G., Hutton, M., and Ashe, K.
H. (2005). Age-dependent neurofib-
rillary tangle formation, neuron loss,
and memory impairment in a mouse
model of human tauopathy (P301L).
J. Neurosci. 25, 10637–10647.
Riccio, D. C., Moody, E. W., and Millin,
P. M. (2002). Reconsolidation recon-
sidered. Integr. Physiol. Behav. Sci. 37,
245–253.
Roberson, E. D., Scearce-Levie, K.,
Palop, J. J., Yan, F., Cheng, I. H.,
Wu, T., Gerstein, H., Yu, G. Q., and
Mucke, L. (2007). Reducing endoge-
nous tau ameliorates amyloid beta-
induced deficits in an Alzheimer’s
disease mouse model. Science 316,
750–754.
Santacruz, K., Lewis, J., Spires, T., Paul-
son, J., Kotilinek, L., Ingelsson, M.,
Guimaraes, A., Deture, M., Rams-
den, M., Mcgowan, E., Forster, C.,
Yue, M., Orne, J., Janus, C., Mari-
ash, A., Kuskowski, M., Hyman, B.,
Hutton, M., and Ashe, K. H. (2005).
Tau suppression in a neurode-
generative mouse model improves
memory function. Science 309,
476–481.
Sato, S., Tatebayashi, Y., Akagi, T., Chui,
D. H., Murayama, M., Miyasaka, T.,
Planel, E., Tanemura, K., Sun, X.,
Hashikawa, T., Yoshioka, K., Ishig-
uro, K., and Takashima, A. (2002).
Aberrant tau phosphorylation by
glycogen synthase kinase-3beta and
JNK3 induces oligomeric tau fibrils
in COS-7 cells. J. Biol. Chem. 277,
42060–42065.
Selkoe, D. J. (1986). Altered structural
proteins in plaques and tangles: what
do they tell us about the biology of
Alzheimer’s disease? Neurobiol. Aging
7, 425–432.
Sereno, L., Coma, M., Rodriguez, M.,
Sanchez-Ferrer, P., Sanchez, M. B.,
Gich, I., Agullo, J. M., Perez, M., Avila,
J.,Guardia-Laguarta, C., Clarimon, J.,
Lleo, A., and Gomez-Isla, T. (2009).
A novel GSK-3beta inhibitor reduces
Alzheimer’s pathology and rescues
neuronal loss in vivo. Neurobiol. Dis.
35, 359–367.
Spires, T. L., Or ne, J. D., Santacruz,
K., Pitstick, R., Carlson, G. A.,
Ashe, K. H., and Hyman, B. T.
(2006). Region-specific dissociation
of neuronal loss and neurofibril-
lary pathology in a mouse model
of tauopathy. Am. J. Pathol. 168,
1598–1607.
Takashima, A. (2008). Hyperphospho-
rylated tau is a cause of neuronal dys-
function in tauopathy. J. Alzheimers
Dis. 14, 371–375.
Takashima, A., Noguchi, K., Michel, G.,
Mercken, M., Hoshi, M., Ishiguro,
K., and Imahori, K. (1996). Exposure
of rat hippocampal neurons to amy-
loid beta peptide (25–35) induces the
inactivation of phosphatidyl inositol-
3 kinase and the activation of tau
protein kinase I/glycogen synthase
kinase-3 beta. Neurosci. Lett. 203,
33–36.
Takashima, A., Noguchi, K., Sato, K.,
Hoshino, T., and Imahori, K. (1993).
Tau protein kinase I is essential for
amyloid beta-protein-induced neu-
rotoxicity. Proc. Natl. Acad. Sci.
U.S.A. 90, 7789–7793.
Tandon, A., Rogaeva, E., Mullan, M.,
and St George-Hyslop, P. H. (2000).
Molecular genetics of Alzheimer’s
disease: the role of beta-amyloid and
the presenilins. Curr. Opin. Neurol.
13, 377–384.
Tsien, J. Z., Huerta, P. T., and Tone-
gawa, S. (1996). The essential role of
hippocampal CA1 NMDA receptor-
dependent synaptic plasticity in spa-
tial memory. Cell 87, 1327–1338.
Walsh, D. M., Klyubin, I., Fadeeva, J. V.,
Cullen, W. K., Anwyl, R.,Wolfe, M. S.,
Rowan, M. J., and Selkoe, D. J. (2002).
Naturally secreted oligomers of amy-
loid beta protein potently inhibit hip-
pocampal long-term potentiation in
vivo. Nature 416, 535–539.
Westerman, M. A., Cooper-Blacketer,
D., Mariash, A., Kotilinek, L.,
Kawar abayashi, T., Younkin, L. H.,
Carlson, G. A., Younkin, S. G.,
and Ashe, K. H. (2002). The rela-
tionship between Abeta and mem-
ory in the Tg2576 mouse model of
Alzheimer’s disease. J. Neurosci. 22,
1858–1867.
Woodgett, J. R. (1990). Molecular
cloning and expression of glycogen
synthase kinase-3/factor A. EMBO J.
8, 2431–2438.
Zhang, X., Heng, X., Li, T., Li, L.,
Yang, D., Du, Y., Doody, R. S.,
and Le, W. (2011). Long-term treat-
ment with lithium alleviates mem-
ory deficits and reduces amyloid-beta
production in an aged Alzheimer’s
disease transgenic mouse model. J.
Alzheimers Dis. 24, 739–749.
Conflict of Interest Statement: The
author declares that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
Received: 17 September 2011; accepted:
22 March 2012; published online: 23
April 2012.
Citation: Takashima A (2012) GSK-3β
and memory formation. Front. Mol.
Neurosci. 5:47. doi: 10.3389/fnmol.2012.
00047
Copyright © 2012 Takashima. This is
an open-access article distributed under
the terms of the Creative Commons
Attribution Non Commercial License,
which permits non-commercial use, dis-
tribution, and reproduction in other
forums, provided the original authors and
source are credited.
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