**4.3 Aβ/SNCA secondary inflammatory cascade**

Although we have indicated that both Aβ and SNCA can activate the TLRs, we have only spoken about the direct activation induced by these molecules on some representatives of the TLR family. However, we must realize that once the TLRs are activated, a full repertory of pro-inflammatory mediators is released to the environment. In this context, Aβ induces the expression of IL-1, IL-6, IL-12, TNF-α, cyclooxygenase 2 (COX2), and the inducible nitric oxide synthase (iNOS) [57]. Additionally, because of the cellular damage caused, it will also induce the release of further DAMPs [26, 27, 58]. Similarly, TLRs activated after SNCA challenge will increase the expression of TNF-α, IL-6, and CXCL1 [49–51]. In the case of SNCA, the cell damage also will

cause the release of several DAMPs. Relevantly, the pro-inflammatory mediators and the subsequent DAMPs induced by Aβ and SNCA are able to further activate additional members of the TLR family, enhancing the inflammatory response. If we take into account that in both pathologies the levels of Aβ and SNCA are steadily increasing, the concept of a chronic inflammatory condition emerges as a potential mechanism to explain the progression of both diseases. Moreover, some of these pro-inflammatory mediators can also have a direct impact on the neuronal activity. Such is the case of the glial TNF-α-mediated expression of the AMPA receptors within the postsynaptic terminal. In this case, the increased production and release of TNF-α by the astrocytes, perhaps induced by the chronic exposure to the inflammatory stimulus, will cause the hyperexcitability of the neurons leading to glutamate excitotoxicity [59–62].

#### **4.4 Microglial priming**

Relevantly, an additional effect caused by Aβ and SNCA should be considered. It has been demonstrated that both molecules are also able to induce a phenomenon termed "microglial priming." In this regard, microglial population which remains in a resting state when exposed to different inflammatory mediators, DAMPs, and/ or PAMPs can differentiate into two activated phenotypes, the M1 and M2. While the M1 is considered as a pro-inflammatory activation state, the M2 is defined as the anti-inflammatory microglial phenotype. Interestingly, it has been evidenced that in the presence of INF-γ and the TLR-mediated signaling, microglia usually undergo M1 transformation. Moreover, when microglia became "primed" usually changes to the M2 phenotype but develops a significant sensibility to new exposures to harmful stimuli, exhibiting an over dimensioned response and causing the abnormal raising of pro-inflammatory molecules because of a shift to the M1 phenotype [63–66]. Thus, Aβ and SNCA seem to be favoring not only the activation of the microglia to the pro-inflammatory phenotype (M1), but also the increase in the responsiveness of the microglia to the harmful stimuli. In both cases, the result will be an over activation of the microglia with the subsequent release of increased levels of pro-inflammatory mediators and ROS, enhancing the damage induced by the initial exposure to Aβ and SNCA [67–69]. Similarly, the chronic exposure to these inflammatory mediators can induce the repolarization of the microglia changing from the M2 to the M1 phenotype [70]. However, additional research is necessary to properly address the significance of microglial priming and the effects of the exposure to different levels of pro-inflammatory stimuli [71]. Indeed, the work conducted by Pourbadie and cols. [72] seems to suggest that low doses of TLR ligands can exert beneficial effects on the neuronal circuitry.

#### **4.5 Mitochondrial dysfunction**

Another feature of both pathologies is the affectation of the mitochondrial functionality. Both Aβ and SNCA have the ability to interact with this critical organelle. While Aβ has been detected outside and inside the mitochondria being able to directly induce the several mitochondria-related apoptotic pathways, such as the B-cell lymphoma 2 (BCL2)-beclin1 (BECN1) complex [73, 74], SNCA can induce the activation of the mitochondrial membrane permeability transition pore, promoting mitochondrial swelling and leading to mitochondrial degradation. Indeed, when SNCA degradation is blocked by means of proteasome inhibition, mitochondria result as one of the first organelles to be affected. Moreover, TOM40, a protein that is part of the mitochondrial import machinery, has proven to be determinant of the SNCA-mediated mitochondrial failure [75–77]. Importantly, one of the most critical end points of the mitochondrial failure is the increased production of ROS

**89**

*Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades…*

which is able to induce the activation of microglia and astrocytes as well as to trigger the inflammatory response mediated by the TLRs. Vice versa, the increased levels of pro-inflammatory mediators, such as TNF-α, induced by the activation of the TLRs by means of the Aβ and SNCA can also lead to mitochondrial dysfunction mainly

**5. Aging and neuroinflammation: self-conditioning to autodestruction?**

As previously mentioned, several works have evidenced the link between aging and neurodegenerative disorders. In the context of neuroinflammation, the immune system decay and a pro-inflammatory status are part of the aging process. Because of the increased levels of circulating inflammatory cytokines and the impaired performance of the cellular components involved in the immune response, a chronic exposure to an inflammatory environment verifies for all the biological systems. Regrettably, it has been demonstrated that the brain exhibits the same age-related pro-inflammatory deviation [84–87]. This general inflammatory status

In general terms, inflammaging is defined by the loss of the inflammatory homeostasis shifting to a pro-inflammatory condition with aging as the determinant factor. Moreover, it has been evidenced that inflammaging is caused by the deregulated function of the inflammasomes, the intracellular structures where several pro-inflammatory mediators are synthetized including several cytokines [84, 88–90]. Moreover, some works have also suggested that inflammaging involves not the deregulation of TLR expression, but the signal cascades triggered after its

On the other hand, inflammaging can also relate with cell senescence. Regrettably, cell senescence also verifies in the immune system and affects the immune cells of both the peripheral system and the CNS. Although astrocytes are believed to be the only cells able to express senescence markers, different researches have evidenced that microglia also exhibit several age-related morphological and biochemical changes. Indeed, the increased levels of activation markers including the cluster of differentiation 11b, 11c, and 14, along with the increased production of TNF-α, IL-1β, IL-6, and reactive oxygen species (ROS) allow to dimension the effect of senescence on the physiology of the immunocompetent cells within the brain [92].

Inflammatory milieu is an extremely complex event. Moreover, it becomes even more complicated when we introduce the neurodegenerative process as part of the inflammatory equation. In this case, the final outcome will not only be determined by the production and release of the pro-inflammatory mediators and the specific responses triggered in the different cell types present in the brain, but it will also depend on the physiological status of these cells. Aging, and the differential exposure

Although aging constitutes a natural process, it has been considered from long ago as the main factor for several age-related conditions. However, we must realize that even when aging implies the progressive decay of several biological systems, the main issue with aging is the time span of exposure to different exogenous and potentially harmful stimuli (http://www.iarc.fr) [79, 80]. If we include the genetic and epigenetic heterogeneity between subjects as another factor to consider, it is almost evident that the aging process will follow different pathways depending on

*DOI: http://dx.doi.org/10.5772/intechopen.86167*

through mitochondrial fragmentation [78].

the particularities of each subject [81–83].

of the brain is currently termed as inflammaging.

activation through different microRNAs [91].

**6. Concluding remarks**

*Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades… DOI: http://dx.doi.org/10.5772/intechopen.86167*

which is able to induce the activation of microglia and astrocytes as well as to trigger the inflammatory response mediated by the TLRs. Vice versa, the increased levels of pro-inflammatory mediators, such as TNF-α, induced by the activation of the TLRs by means of the Aβ and SNCA can also lead to mitochondrial dysfunction mainly through mitochondrial fragmentation [78].

#### **5. Aging and neuroinflammation: self-conditioning to autodestruction?**

Although aging constitutes a natural process, it has been considered from long ago as the main factor for several age-related conditions. However, we must realize that even when aging implies the progressive decay of several biological systems, the main issue with aging is the time span of exposure to different exogenous and potentially harmful stimuli (http://www.iarc.fr) [79, 80]. If we include the genetic and epigenetic heterogeneity between subjects as another factor to consider, it is almost evident that the aging process will follow different pathways depending on the particularities of each subject [81–83].

As previously mentioned, several works have evidenced the link between aging and neurodegenerative disorders. In the context of neuroinflammation, the immune system decay and a pro-inflammatory status are part of the aging process. Because of the increased levels of circulating inflammatory cytokines and the impaired performance of the cellular components involved in the immune response, a chronic exposure to an inflammatory environment verifies for all the biological systems. Regrettably, it has been demonstrated that the brain exhibits the same age-related pro-inflammatory deviation [84–87]. This general inflammatory status of the brain is currently termed as inflammaging.

In general terms, inflammaging is defined by the loss of the inflammatory homeostasis shifting to a pro-inflammatory condition with aging as the determinant factor. Moreover, it has been evidenced that inflammaging is caused by the deregulated function of the inflammasomes, the intracellular structures where several pro-inflammatory mediators are synthetized including several cytokines [84, 88–90]. Moreover, some works have also suggested that inflammaging involves not the deregulation of TLR expression, but the signal cascades triggered after its activation through different microRNAs [91].

On the other hand, inflammaging can also relate with cell senescence. Regrettably, cell senescence also verifies in the immune system and affects the immune cells of both the peripheral system and the CNS. Although astrocytes are believed to be the only cells able to express senescence markers, different researches have evidenced that microglia also exhibit several age-related morphological and biochemical changes. Indeed, the increased levels of activation markers including the cluster of differentiation 11b, 11c, and 14, along with the increased production of TNF-α, IL-1β, IL-6, and reactive oxygen species (ROS) allow to dimension the effect of senescence on the physiology of the immunocompetent cells within the brain [92].

#### **6. Concluding remarks**

Inflammatory milieu is an extremely complex event. Moreover, it becomes even more complicated when we introduce the neurodegenerative process as part of the inflammatory equation. In this case, the final outcome will not only be determined by the production and release of the pro-inflammatory mediators and the specific responses triggered in the different cell types present in the brain, but it will also depend on the physiological status of these cells. Aging, and the differential exposure

*Toll-like Receptors*

**4.4 Microglial priming**

cause the release of several DAMPs. Relevantly, the pro-inflammatory mediators and the subsequent DAMPs induced by Aβ and SNCA are able to further activate additional members of the TLR family, enhancing the inflammatory response. If we take into account that in both pathologies the levels of Aβ and SNCA are steadily increasing, the concept of a chronic inflammatory condition emerges as a potential mechanism to explain the progression of both diseases. Moreover, some of these pro-inflammatory mediators can also have a direct impact on the neuronal activity. Such is the case of the glial TNF-α-mediated expression of the AMPA receptors within the postsynaptic terminal. In this case, the increased production and release of TNF-α by the astrocytes, perhaps induced by the chronic exposure to the inflammatory stimulus, will cause the

hyperexcitability of the neurons leading to glutamate excitotoxicity [59–62].

Relevantly, an additional effect caused by Aβ and SNCA should be considered. It has been demonstrated that both molecules are also able to induce a phenomenon termed "microglial priming." In this regard, microglial population which remains in a resting state when exposed to different inflammatory mediators, DAMPs, and/ or PAMPs can differentiate into two activated phenotypes, the M1 and M2. While the M1 is considered as a pro-inflammatory activation state, the M2 is defined as the anti-inflammatory microglial phenotype. Interestingly, it has been evidenced that in the presence of INF-γ and the TLR-mediated signaling, microglia usually undergo M1 transformation. Moreover, when microglia became "primed" usually changes to the M2 phenotype but develops a significant sensibility to new exposures to harmful stimuli, exhibiting an over dimensioned response and causing the abnormal raising of pro-inflammatory molecules because of a shift to the M1 phenotype [63–66]. Thus, Aβ and SNCA seem to be favoring not only the activation of the microglia to the pro-inflammatory phenotype (M1), but also the increase in the responsiveness of the microglia to the harmful stimuli. In both cases, the result will be an over activation of the microglia with the subsequent release of increased levels of pro-inflammatory mediators and ROS, enhancing the damage induced by the initial exposure to Aβ and SNCA [67–69]. Similarly, the chronic exposure to these inflammatory mediators can induce the repolarization of the microglia changing from the M2 to the M1 phenotype [70]. However, additional research is necessary to properly address the significance of microglial priming and the effects of the exposure to different levels of pro-inflammatory stimuli [71]. Indeed, the work conducted by Pourbadie and cols. [72] seems to suggest that low doses of TLR ligands can exert beneficial effects on the neuronal

Another feature of both pathologies is the affectation of the mitochondrial functionality. Both Aβ and SNCA have the ability to interact with this critical organelle. While Aβ has been detected outside and inside the mitochondria being able to directly induce the several mitochondria-related apoptotic pathways, such as the B-cell lymphoma 2 (BCL2)-beclin1 (BECN1) complex [73, 74], SNCA can induce the activation of the mitochondrial membrane permeability transition pore, promoting mitochondrial swelling and leading to mitochondrial degradation. Indeed, when SNCA degradation is blocked by means of proteasome inhibition, mitochondria result as one of the first organelles to be affected. Moreover, TOM40, a protein that is part of the mitochondrial import machinery, has proven to be determinant of the SNCA-mediated mitochondrial failure [75–77]. Importantly, one of the most critical end points of the mitochondrial failure is the increased production of ROS

**88**

circuitry.

**4.5 Mitochondrial dysfunction**

to xenobiotics, will certainly determine the health status of the cells and its ability to answer properly to the inflammatory stimulus and to resist a pro-inflammatory condition. At the basis of all these processes, the molecular mechanisms triggered by the TLRs play a critical role during both AD and PD establishment and progression. Moreover, through the cross talk with additional signaling pathways, TLR cascade is able to interfere with different aspects of the cell physiology from energy production to cytoskeleton rearrangements. On the other hand, less is known regarding other representatives of the TLR family and their impact on AD/PD pathophysiology. For example, some evidence seems to suggest that while TLR9 will exert a protective effect in the context of the neurodegenerative process driven by Aβ and SNCA, TLR3 will also enhance the release of pro-inflammatory mediators [93].

To date, significant evidence seems to confirm the key role of the inflammatory milieu in the neurodegenerative process and this situation should prompt researchers to increase their efforts to understand this cascade of events and to unveil the missing points of an inflammatory-based hypothesis of the neurodegenerative disorders.
