ReviewWnt signaling in Alzheimer's disease: Up or down, that is the question
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.
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