**4. Wnt signalling in the context of AD and PD anti-inflammatory therapeutics**

Currently, neurodegenerative disorders, especially AD and PD, are considered a major concern in public health because of the ageing of the global population. Although some progress has been made regarding pharmacological strategies, regrettably, no effective therapies are currently available to stop or reverse these pathologies. Among the alternative approaches to overcome such situations, the identification and further modulation of key cellular pathways involved in the pathophysiology of neurodegenerative disorders should not be underestimated. In this regard, even when it is well recognised that inflammation is one of the most relevant features of AD and PD, anti-inflammatory therapies have remained overlooked, although some epidemiological data have suggested a significant effect in terms of risk reduction with the use of some nonsteroidal anti-inflammatory drugs (NSAIDs) [95, 96]. Interestingly, the main effects related to the use of such a family of drugs have been observed prior to the onset of pathology; however, the efficacy of an anti-inflammatory therapy cannot be fully discarded. Indeed, the reasons behind the failure of some clinical trials exploring the beneficial effects of NSAIDs in AD and PD have not been properly addressed [97]. Moreover, a quick search of scientific databases, such as PubMed, will return over 3000 and 1000 entries for AD and PD, respectively, when both "anti-inflammatory therapy" and "AD/PD" are used as search terms. This issue not only reinforces the fact that inflammation is a key element of both pathologies but also indicates that the inflammatory cascade is closely related to several signalling pathways that have been linked to the pathophysiology of these diseases. Regrettably, our understanding of these mechanisms is incomplete, limiting our capacity to properly address and exploit such relationships.

but also act as a relevant player in the ageing process. In this regard, we have recently demonstrated that the loss of Wnt signalling favours the appearance of several pathological markers linked to AD in a wild-type murine model [102]. Moreover, we found that Wnt signalling is involved in the neuronal energy metabolism and that its activation rescues energy imbalance because of improved glucose utilisation [103]. On the other hand, Wnt signalling also plays a relevant role in PD. It has been demonstrated that LRRK2 can interact with several members of the β-catenin destruction complex, including Dvl, Axin, GSK3β and β-catenin [104]. Similarly, PRKN is related to the ubiquitination of β-catenin, playing a direct role in the modulation of this pathway [105]. The relevance of such regulation has prompted some researchers to propose the pharmacological modulation of Wnt signalling as a relevant target in PD [106]. Complimentary to these well-established effects, Wnt signalling has also been

Molecular Basis of Neurodegeneration: Lessons from Alzheimer's and Parkinson's Diseases

http://dx.doi.org/10.5772/intechopen.81270

57

Although it could be considered circumstantial, the inflammatory status and Wnt signalling are inversely correlated during the ageing process; in other words, while the pro-inflammatory status increases with age, Wnt signalling decreases. Of course, additional signalling pathways are impaired during ageing; however, the fact that Wnt is able to modulate the NF-kB pathway strongly suggests that this particular pathway has a direct impact on the immune/inflammatory response observed during the ageing process. Moreover, it should be considered that even when it is well accepted that canonical Wnt signalling has anti-inflammatory activity and the non-canonical pathway exerts a pro-inflammatory effect, these opposing functions can be carried out by the same ligand, such as Wnt5a [21, 101]. This latter finding also suggests that depending on the physiological or pathological status of the biological system, Wnt components can exert different modulatory effects to contribute to the maintenance of system balance. In contrast, inflammation can also modulate Wnt activity. In this regard, TLR activation can downregulate the canonical Wnt signalling pathway. While TLR4 causes the blockade of the Fz-LRP5/6 complex [107], MyD88-mediated TLR activity activates nemo-like kinase (NLK), which interacts with the nuclear β-catenin-TCF/Lef complex. Similarly, MyD88-independent TLR signalling activates IKKe/TBK1, which can directly phosphorylate Akt, leading to GSK3β

inhibition and blocking the activity of the β-catenin destruction complex [108–111].

Although evidence demonstrates a close relationship between Wnt signalling and the inflammatory process, our knowledge regarding this issue remains limited. Moreover, the already proven involvement and the critical role that Wnt signalling seems to play in different aspects of physiological and pathological cellular mechanisms certainly indicate that this pathway needs to be investigated deeply to properly assess the effects of finely modulating Wnt signalling, including its potentially beneficial effects in the context of the inflammatory response. In this regard, part of our work suggests that lithium and andrographolide, both well-established canonical Wnt agonists that act via GSK3β inhibition, can play a relevant role not only under pathological conditions but also as exogenous support of a healthy ageing process by reducing several markers of unhealthy conditions, including neuroinflammation [112].

linked to modulation and crosstalk within the inflammatory cascade.

**4.2. Wnt signalling and the inflammatory pathway**

In this regard, over several decades, our laboratory has been working on Wnt signalling, a master cellular pathway involved in both physiological and pathological conditions. The activity of Wnt signalling varies with ageing depending on the tissue [98]. Specifically, in the brain, an overall downregulation of the Wnt pathway is observed, suggesting that some of the impairments associated with age might be mediated by this Wnt decay [98, 99]. Accordingly, this situation suggests that the rescuing of its activity might be a promising strategy to prevent and alleviate some of the pathological features of AD and PD.

### **4.1. Wnt signalling pathway**

From the initial steps during embryogenesis to the less explored adult neurogenesis, the Wnt pathway constitutes the core molecular signalling pathway of cellular physiology. Its relevance is demonstrated by the evolutionary conservation of this system among different species, and its potentialities are cross-linked with the outcome of different neurodegenerative disorders, including AD and PD [100, 101].

The Wnt pathway is commonly divided into two canonical or β-catenin-dependent and noncanonical pathways, with the latter further divided into Wnt/Ca++ and planar cell polarity (JNK). Briefly, in the canonical pathway, the Wnt ligands bind to Frizzled receptor/lowdensity lipoprotein receptor-related protein 5/6 (Fz/LRP5/6) and the subsequent activation of Dishevelled. This situation leads to disassembly of the β-catenin destruction complex comprising adenoma polyposis coli (APC), Axin, GSK3β and casein kinase 1 (CK1), leaving β-catenin free to translocate to the nucleus and initiate transcription of the Wnt target genes together with the T-cell factor/lymphoid enhancer factor (TCF/Lef) transcription factor. In the absence of Wnt ligands, the destruction complex remains active, and GSK3b phosphorylates β-catenin, causing its proteasomal degradation. On the other hand, in Wnt/planar cell polarity, the binding of Wnt ligands will induce cytoskeletal rearrangements via JNK-mediated mechanisms; in the Wnt/Ca++ pathway, ligand binding induces the release of Ca2+ from the ER, causing the activation of several calcium-related proteins, such as protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase (Ca2+/CamKII) [21, 100].

Additionally, the different cascades described for Wnt signalling can interact with several cellular pathways, including the forkhead box O (FOXO), Notch and hypoxia-inducible factor 1 alpha (HIF1α) pathways [93]. Precisely, the wide range of molecular interactions established by Wnt signalling serves to explain how its altered activity can not only favour or directly induce different pathological conditions, including neurodegenerative disorders and cancer, but also act as a relevant player in the ageing process. In this regard, we have recently demonstrated that the loss of Wnt signalling favours the appearance of several pathological markers linked to AD in a wild-type murine model [102]. Moreover, we found that Wnt signalling is involved in the neuronal energy metabolism and that its activation rescues energy imbalance because of improved glucose utilisation [103]. On the other hand, Wnt signalling also plays a relevant role in PD. It has been demonstrated that LRRK2 can interact with several members of the β-catenin destruction complex, including Dvl, Axin, GSK3β and β-catenin [104]. Similarly, PRKN is related to the ubiquitination of β-catenin, playing a direct role in the modulation of this pathway [105]. The relevance of such regulation has prompted some researchers to propose the pharmacological modulation of Wnt signalling as a relevant target in PD [106]. Complimentary to these well-established effects, Wnt signalling has also been linked to modulation and crosstalk within the inflammatory cascade.

#### **4.2. Wnt signalling and the inflammatory pathway**

a quick search of scientific databases, such as PubMed, will return over 3000 and 1000 entries for AD and PD, respectively, when both "anti-inflammatory therapy" and "AD/PD" are used as search terms. This issue not only reinforces the fact that inflammation is a key element of both pathologies but also indicates that the inflammatory cascade is closely related to several signalling pathways that have been linked to the pathophysiology of these diseases. Regrettably, our understanding of these mechanisms is incomplete, limiting our capacity to

In this regard, over several decades, our laboratory has been working on Wnt signalling, a master cellular pathway involved in both physiological and pathological conditions. The activity of Wnt signalling varies with ageing depending on the tissue [98]. Specifically, in the brain, an overall downregulation of the Wnt pathway is observed, suggesting that some of the impairments associated with age might be mediated by this Wnt decay [98, 99]. Accordingly, this situation suggests that the rescuing of its activity might be a promising strategy to prevent and

From the initial steps during embryogenesis to the less explored adult neurogenesis, the Wnt pathway constitutes the core molecular signalling pathway of cellular physiology. Its relevance is demonstrated by the evolutionary conservation of this system among different species, and its potentialities are cross-linked with the outcome of different neurodegenera-

The Wnt pathway is commonly divided into two canonical or β-catenin-dependent and noncanonical pathways, with the latter further divided into Wnt/Ca++ and planar cell polarity (JNK). Briefly, in the canonical pathway, the Wnt ligands bind to Frizzled receptor/lowdensity lipoprotein receptor-related protein 5/6 (Fz/LRP5/6) and the subsequent activation of Dishevelled. This situation leads to disassembly of the β-catenin destruction complex comprising adenoma polyposis coli (APC), Axin, GSK3β and casein kinase 1 (CK1), leaving β-catenin free to translocate to the nucleus and initiate transcription of the Wnt target genes together with the T-cell factor/lymphoid enhancer factor (TCF/Lef) transcription factor. In the absence of Wnt ligands, the destruction complex remains active, and GSK3b phosphorylates β-catenin, causing its proteasomal degradation. On the other hand, in Wnt/planar cell polarity, the binding of Wnt ligands will induce cytoskeletal rearrangements via JNK-mediated mechanisms; in the Wnt/Ca++ pathway, ligand binding induces the release of Ca2+ from the ER, causing the activation of several calcium-related proteins, such as protein kinase C (PKC) and

Additionally, the different cascades described for Wnt signalling can interact with several cellular pathways, including the forkhead box O (FOXO), Notch and hypoxia-inducible factor 1 alpha (HIF1α) pathways [93]. Precisely, the wide range of molecular interactions established by Wnt signalling serves to explain how its altered activity can not only favour or directly induce different pathological conditions, including neurodegenerative disorders and cancer,

calcium/calmodulin-dependent protein kinase (Ca2+/CamKII) [21, 100].

properly address and exploit such relationships.

alleviate some of the pathological features of AD and PD.

tive disorders, including AD and PD [100, 101].

**4.1. Wnt signalling pathway**

56 Recent Advances in Neurodegeneration

Although it could be considered circumstantial, the inflammatory status and Wnt signalling are inversely correlated during the ageing process; in other words, while the pro-inflammatory status increases with age, Wnt signalling decreases. Of course, additional signalling pathways are impaired during ageing; however, the fact that Wnt is able to modulate the NF-kB pathway strongly suggests that this particular pathway has a direct impact on the immune/inflammatory response observed during the ageing process. Moreover, it should be considered that even when it is well accepted that canonical Wnt signalling has anti-inflammatory activity and the non-canonical pathway exerts a pro-inflammatory effect, these opposing functions can be carried out by the same ligand, such as Wnt5a [21, 101]. This latter finding also suggests that depending on the physiological or pathological status of the biological system, Wnt components can exert different modulatory effects to contribute to the maintenance of system balance. In contrast, inflammation can also modulate Wnt activity. In this regard, TLR activation can downregulate the canonical Wnt signalling pathway. While TLR4 causes the blockade of the Fz-LRP5/6 complex [107], MyD88-mediated TLR activity activates nemo-like kinase (NLK), which interacts with the nuclear β-catenin-TCF/Lef complex. Similarly, MyD88-independent TLR signalling activates IKKe/TBK1, which can directly phosphorylate Akt, leading to GSK3β inhibition and blocking the activity of the β-catenin destruction complex [108–111].

Although evidence demonstrates a close relationship between Wnt signalling and the inflammatory process, our knowledge regarding this issue remains limited. Moreover, the already proven involvement and the critical role that Wnt signalling seems to play in different aspects of physiological and pathological cellular mechanisms certainly indicate that this pathway needs to be investigated deeply to properly assess the effects of finely modulating Wnt signalling, including its potentially beneficial effects in the context of the inflammatory response. In this regard, part of our work suggests that lithium and andrographolide, both well-established canonical Wnt agonists that act via GSK3β inhibition, can play a relevant role not only under pathological conditions but also as exogenous support of a healthy ageing process by reducing several markers of unhealthy conditions, including neuroinflammation [112].
