Review
Wnt signaling in Alzheimer's disease: Up or down, that is the question

https://doi.org/10.1016/j.arr.2008.11.003Get rights and content

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by amyloid-β (Aβ) plaques and hyperphosphorylated tau accumulation. AD occurs sporadically (SAD), or is caused by hereditary missense mutations in the amyloid precursor protein (APP) or presenilin-1 and -2 (PSEN1 and PSEN2) genes, leading to early-onset familial AD (FAD). Accumulating evidence points towards a role for altered Wnt/β-catenin-dependent signaling in the etiology of both forms of AD. Presenilins are involved in modulating β-catenin stability; therefore FAD-linked PSEN-mediated effects can deregulate the Wnt pathway. Genetic variations in the low-density lipoprotein receptor-related protein 6 and apolipoprotein E in AD have been associated with reduced Wnt signaling. In addition, tau phosphorylation is mediated by glycogen synthase kinase-3 (GSK-3), a key antagonist of the Wnt pathway.

In this review, we discuss Wnt/β-catenin signaling in both SAD and FAD, and recapitulate which of its aberrant functions may be critical for (F)AD pathogenesis. We discuss the intriguing possibility that Aβ toxicity may downregulate the Wnt/β-catenin pathway, thereby upregulating GSK-3 and consequent tau hyperphosphorylation, linking Aβ and tangle pathology. The currently available evidence implies that disruption of tightly regulated Wnt signaling may constitute a key pathological event in AD. In this context, drug targets aimed at rescuing Wnt signaling may prove to be a constructive therapeutic strategy for AD.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. The majority of AD cases occur sporadically (SAD), however, in a subset of patients with familial-linked AD (FAD), a genetic mutation is the underlying cause of the disease. In both SAD and FAD, the abnormal formation of intracellular as well as extracellular protein aggregates represents the central neuropathological hallmark. The intraneuronal neurofibrillary tangles (NFTs) are composed of insoluble hyperphosphorylated forms of the microtubule-associated protein tau (MAPT) (Geschwind, 2003). Extracellular protein deposits consist of initially soluble 40–42-amino acids long amyloid-β (Aβ) peptides. When aggregated into insoluble high molecular weight fibrils, these Aβ depositions represent the most prominent neuropathological feature of AD, i.e. Aβ plaques. According to the amyloid-cascade hypothesis of AD, production of the more aggregate-prone Aβ42 is considered to be the key event in AD pathology (Hardy and Selkoe, 2002).

Besides ageing being the main risk factor for developing SAD, the etiology of this heterogeneous disease remains largely unclear and comprises a complex interaction of both genetic and non-genetic risk factors. Given the course of the disease encompassing a lengthy time period from initial molecular hits to the overt disease manifestation, subtle changes in cellular processes or pathways are likely to accumulate, act slowly at a systemic level and/or rapidly in a cell autonomous manner in neurons. Hence, it remains difficult to pinpoint the primary molecular “hits”. Although a strong heritable component has been shown to underlie SAD susceptibility in a large-scale twin study (Gatz et al., 2006), very few gene loci have unequivocally been linked to the disease. A strong association between the apolipoprotein E-4 (APOE-4) allele and SAD has been reported by various research groups (Corder et al., 1993, Poirier et al., 1993, Strittmatter et al., 1993) and is widely accepted as the major genetic risk factor for AD. APOE acts as a cholesterol transporter in the brain and may be essential in the process of Aβ deposition and plaque formation (Poirier, 1994, Holtzman et al., 2000). APOE-4 appears to increase the risk of late-onset AD by lowering the age of onset. Albeit the precise molecular mechanisms underlying this disease-promoting effect have not yet been determined, it has been proposed that the E-4 allele is less efficient in maintaining the integrity of lipoprotein homeostasis in neurons, thereby compromising neuronal repair processes and synaptic plasticity (Cedazo-Minguez, 2007). Additionally, genetic variations in the transmembrane receptor low-density lipoprotein receptor-related protein 6 (LRP6) have also been reported as a risk factor for SAD (De Ferrari et al., 2007). Several other confounding factors in AD pathogenesis include aberrant cell cycling, deregulation of neuronal energy metabolism due to mitochondrial dysfunction, inflammatory mechanisms, oxidative stress, and proteasome dysfunction (Walsh and Aisen, 2004, Gibson and Huang, 2005, Reddy and Beal, 2005, Webber et al., 2005, van Tijn et al., 2008).

FAD, the early-onset inherited form of AD, is caused by rare autosomal dominant missense mutations in the amyloid precursor protein (APP) or the presenilin-1 and -2 (PSEN1 and PSEN2) genes. Presenilins are 9-pass transmembrane proteins forming the enzymatically active core of the γ-secretase complex involved in the proteolytic cleavage of type-1 transmembrane receptors, including APP and Notch (De Strooper et al., 1999). Concerted β- and γ-secretase-mediated cleavage of APP results in the release of Aβ40–42 peptides. Although Aβ42 is believed to be the more amyloidogenic form, the Aβ40 peptide has an important role in the maturation of dense cored plaques, without directly affecting disease progression (Kumar-Singh et al., 2000). FAD-linked APP mutations are clustered in close proximity to the β- and γ-secretase cleavage sites and generally result in a less aggressive course of the disease than FAD-linked PSEN mutations. FAD-PSEN mutations are distributed throughout the PSEN1 and PSEN2 genes and account for most cases of FAD. These mutations typically result in dysfunctional Aβ production, preferentially mediating an increase in the Aβ42/Aβ40 ratio (Bentahir et al., 2006, Kumar-Singh et al., 2006). It has been proposed that the increased Aβ42/Aβ40 ratio results from a partial PSEN loss-of-function, manifesting itself as a spatial shift of γ-secretase cleavage (Shen and Kelleher, 2007). Nevertheless, the exact mechanism of Aβ toxicity in either FAD or SAD remains to be elucidated.

Several lines of evidence imply a neurotoxic effect of Aβ that is independent of its aggregation into senile plaques (Hsia et al., 1999, Lue et al., 1999, McLean et al., 1999, Heinitz et al., 2006), suggesting that soluble oligomers of Aβ42 are more toxic than its aggregated forms and may signify the major force in the induction of pathogenic processes central to AD (LaFerla et al., 2007). In vitro evidence shows that soluble oligomeric, but not fibrillar, Aβ42 induces toxicity in cholinergic neurons (Heinitz et al., 2006). Consistently, several studies reported that levels of soluble Aβ, including soluble oligomers, correlate much better with cognitive decline than do Aβ plaque counts (Lue et al., 1999, McLean et al., 1999, Naslund et al., 2000). In contrast to aggregated forms of Aβ, small oligomers would be able to diffuse into synaptic clefts thereby mediating synaptic dysfunction. Alternatively, the diffusible Aβ oligomers may interfere with intracellular signaling pathways and adversely affect neuronal viability. Therefore, soluble oligomers are likely better candidates to impair synaptic plasticity as compared to plaques and hence are thought to play a principal role in pre-symptomatic, early stages of the AD process, before the onset of plaque pathology (Haass and Selkoe, 2007). Accordingly, plaque formation may reduce the toxicity of soluble Aβ by recruiting the peptide into extracellular amyloid aggregates, thereby preventing interference with normal intracellular signaling pathways. As a dynamic exchange between soluble and aggregated forms of Aβ may be a process crucial to the AD pathological cascade, possibly acting differentially at different disease stages, it remains difficult to pinpoint soluble oligomers as the sole culprit leading to neurotoxic effects.

Besides the multiple factors implicated in AD pathogenesis, increasing evidence points towards a role for deregulated Wnt signaling in the etiology of both forms of AD. Concerning FAD, increasing evidence supports the concept that PSEN1 is an important negative regulator of Wnt key effector β-catenin. However, conflicting results render it difficult to determine the true effect of FAD mutations on β-catenin-dependent Wnt output. In SAD, different components of the Wnt signaling pathway are affected, mostly leading to attenuation of the pathway's output (Caricasole et al., 2004, Caruso et al., 2006, De Ferrari et al., 2007). Given that tight control of Wnt signaling is a prerequisite for normal neural development as well as for the maintenance of neuronal homeostasis and synaptic plasticity in adults (Logan and Nusse, 2004, Speese and Budnik, 2007), altered Wnt signaling may represent an important aspect in the pathology of AD. Wnt signaling may also be implicated in contributing to impaired cognition prior to overt disease symptoms. Indeed, this possibility is underscored by the findings that the canonical Wnt pathway is potentially involved in the regulation of neurotransmitter release and plays a role in long-term plasticity and synaptic transmission (Speese and Budnik, 2007). This could implicate a subtle digression from normal Wnt pathway regulation in reduced synaptic function and plasticity, ultimately compromising memory in AD. Signaling pathways that are crucial in neural development remain functional, but tightly controlled in adulthood, and may thus contribute to neurodegenerative diseases as they are either reactivated or perturbed in later life (Selkoe and Kopan, 2003). In this review, we discuss and summarize the role of Wnt signaling in AD. Based on the currently available experimental data (Table 1), we hypothesize that misregulation of Wnt signaling is potentially one of the underlying factors contributing to the neuropathogenesis of both FAD and SAD. We propose how a disrupted Wnt signal may form a direct link between Aβ toxicity and hyperphosphorylation of tau, ultimately leading to impaired synaptic plasticity or neuronal degeneration.

Section snippets

Ins and outs of canonical Wnt signaling

Wnt proteins are secreted polypeptide growth factors with a high degree of evolutionary conservation. In the developing brain, Wnt signaling is crucial in cell fate determination, neural stem cell maintenance, axonogenesis and establishment of brain polarity (Ciani and Salinas, 2005). Tight control of Wnt signaling is a prerequisite for maintenance of neuronal homeostasis while disruption of this pathway has been implicated in neurodevelopmental as well as in neurodegenerative diseases,

Aberrant regulation of Wnt/β-catenin signaling in AD

Studies concerning Wnt signaling in AD indicate that Wnt may be affected at different levels in either SAD or FAD. Below we discuss how Wnt signaling may be deregulated at the receptor level mainly in SAD, or at the level of cytosolic β-catenin mainly in FAD. An overview on published data regarding aberrant Wnt signaling is provided in Table 1.

Therapeutics for AD: inhibition of GSK-3 and stimulation of Wnt

As increasing evidence implicates canonical Wnt signaling in AD pathology, modulation of this pathway may prove to be beneficial. Deregulation of Wnt/β-catenin-dependent processes, such as neuronal survival and synaptic transmission, potentially increase neuronal sensitivity to Aβ toxicity and tau pathology. Alvares et al. reported that exposure to Aβ induces a decrease in cytoplasmic β-catenin as well as decreased transcription of Wnt target gene engrailed-1 in vitro, ultimately resulting in

Conclusion

AD is a complex neurodegenerative disease, neuropathologically characterized by the presence of Aβ plaques and NFTs. While both genetic and environmental factors are implicated in the etiology of AD, the molecular mechanisms underlying neuronal dysfunction and neurodegeneration still remain to be elucidated. As reviewed here, increasing evidence suggests a role for unbalanced Wnt/β-catenin signaling in neurodegeneration and impaired neuronal plasticity, as seen in AD. It is of importance to

Acknowledgements

Paula van Tijn is supported by the ‘Internationale Stichting Alzheimer Onderzoek’ (ISAO), grant number #07508 to Zivkovic laboratory. Zivkovic laboratory acknowledges support from Netherlands Brain Foundation, grant numbers 15F07(2).03 and 13F05(2).36.

References (133)

  • G.G. Farias et al.

    The anti-inflammatory and cholinesterase inhibitor bifunctional compound IBU-PO protects from beta-amyloid neurotoxicity by acting on Wnt signaling components

    Neurobiol. Dis.

    (2005)
  • D.H. Geschwind

    Tau phosphorylation, tangles, and neurodegeneration: the chicken or the egg?

    Neuron

    (2003)
  • G.E. Gibson et al.

    Oxidative stress in Alzheimer's disease

    Neurobiol. Aging

    (2005)
  • M.D. Gordon et al.

    Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors

    J. Biol. Chem.

    (2006)
  • K.A. Guger et al.

    A mode of regulation of beta-catenin signaling activity in Xenopus embryos independent of its levels

    Dev. Biol.

    (2000)
  • M. Hong et al.

    Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3

    J. Biol. Chem.

    (1997)
  • G.R. Jackson et al.

    Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila

    Neuron

    (2002)
  • H. Jiang et al.

    Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators

    Cell

    (2005)
  • D.E. Kang et al.

    Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis

    Cell

    (2002)
  • S.H. Koh et al.

    Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3

    Brain Res.

    (2008)
  • N. Kozlovsky et al.

    GSK-3 and the neurodevelopmental hypothesis of schizophrenia

    Eur. Neuropsychopharmacol.

    (2002)
  • V.E. Krupnik et al.

    Functional and structural diversity of the human Dickkopf gene family

    Gene

    (1999)
  • C. Liu et al.

    Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism

    Cell

    (2002)
  • S. Lovestone et al.

    Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells

    Curr. Biol.

    (1994)
  • L.F. Lue et al.

    Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease

    Am. J. Pathol.

    (1999)
  • M.H. Magdesian et al.

    Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling

    J. Biol. Chem.

    (2008)
  • M. Molenaar et al.

    XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos

    Cell

    (1996)
  • J.R. Munoz-Montano et al.

    Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons

    FEBS Lett.

    (1997)
  • M. Murayama et al.

    Direct association of presenilin-1 with beta-catenin

    FEBS Lett.

    (1998)
  • J. Poirier

    Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease

    Trends Neurosci.

    (1994)
  • J. Poirier et al.

    Apolipoprotein E polymorphism and Alzheimer's disease

    Lancet

    (1993)
  • W.J. Ray et al.

    Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch

    J. Biol. Chem.

    (1999)
  • P.H. Reddy et al.

    Are mitochondria critical in the pathogenesis of Alzheimer's disease?

    Brain Res. Brain Res. Rev.

    (2005)
  • P. Salins et al.

    Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling

    Neurosci. Lett.

    (2007)
  • C. Scali et al.

    Inhibition of Wnt signaling, modulation of Tau phosphorylation and induction of neuronal cell death by DKK1

    Neurobiol. Dis.

    (2006)
  • S. Amit et al.

    Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway

    Genes Dev.

    (2002)
  • W.G. Annaert et al.

    Presenilin 1 controls gamma-secretase processing of amyloid precursor protein in pre-golgi compartments of hippocampal neurons

    J. Cell Biol.

    (1999)
  • A.A. Asuni et al.

    GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt

    Eur. J. Neurosci.

    (2006)
  • L. Baki et al.

    Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling

    J. Neurosci.

    (2008)
  • L. Baki et al.

    PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations

    EMBO J.

    (2004)
  • C. Ballatore et al.

    Tau-mediated neurodegeneration in Alzheimer's disease and related disorders

    Nat. Rev. Neurosci.

    (2007)
  • M. Bentahir et al.

    Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms

    J. Neurochem.

    (2006)
  • O. Berezovska et al.

    Notch is expressed in adult brain, is coexpressed with presenilin-1, and is altered in Alzheimer disease

    J. Neuropathol. Exp. Neurol.

    (1998)
  • E.M. Blalock et al.

    Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • E. Brunner et al.

    pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila

    Nature

    (1997)
  • A. Caricasole et al.

    Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain

    J. Neurosci.

    (2004)
  • A. Caruso et al.

    Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells

    J. Neurochem.

    (2006)
  • R.A. Cavallo et al.

    Drosophila Tcf and Groucho interact to repress Wingless signalling activity

    Nature

    (1998)
  • A. Cedazo-Minguez

    Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities

    J. Cell. Mol. Med.

    (2007)
  • G. Chen et al.

    The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS

    J. Neurochem.

    (1999)
  • Cited by (113)

    • Role of Wnt signaling in synaptic plasticity and memory

      2022, Neurobiology of Learning and Memory
    View all citing articles on Scopus
    View full text