**1. Brief introduction to ageing**

Undoubtedly, the increased life expectancy of the global population constitutes a major achievement of the modern world. However, it has also opened a gate for the development of age-related conditions that are far from completely understood. In this regard, age-related diseases, particularly neurodegenerative disorders, currently constitute a public health focal point. Accordingly, in recent years, much attention has been focused on understanding both the physiology of ageing and the critical events driving pathological ageing with the subsequent development of different age-related disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) [1].

is considered one of the major components of the neurodegenerative process observed in both AD and PD. Importantly, beyond the energy impairment, mitochondrial alterations contribute significantly to the increased production of ROS/RNS, increasing the oxidative pressure on

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

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

47

On the other hand, it has been well established that chronic exposure to increased levels of prooxidant species leads to the concurrent activation of the immune system and triggering of the inflammatory cascade, both further sustained by the release of several pro-inflammatory mediators, such as several interleukins (IL-1, IL-6, IL-8) and interferon-γ (IFN-γ) [16–19]. Moreover, inflammation and the immune response both involve nuclear factor κb (NFκb), a common point that crosslinks both responses. While toll-like receptors (TLRs), which are activated by different subcellular molecular components (damage-associated molecular patterns, DAMPs), signal through NFκb to release several pro-inflammatory cytokines, leading to activation of the immune response, the very same NFκb constitutes an oxidative stress sensor, connecting the increased levels of ROS/RNS with activation of the inflammatory cascade [20, 21]. Additionally, it must be considered that immunocompetence is usually compromised in aged individuals, and several authors have shown that this decay is closely linked to the altered epigenetic control of several immune-related genes [22–24]. Altogether, this evidence suggests that the difference between "normal" and pathological ageing lies in the subtle equilibrium of different homeostatic

**Figure 1.** Homeostatic balance against pathological ageing, Alzheimer's disease (AD) and Parkinson's disease (PD). The delicate balance that sustains healthy ageing can be broken under several conditions. Environmental challenges, pathological processes, such as AD and PD, or ageing itself might introduce further pressure in different homeostatic systems, including the immune and redox systems. Moreover, the complex network of molecular alterations, organelle dysfunction and cellular signalling, among others, increases the difficulty of properly addressing the cloudy edge

between healthy ageing, pathological ageing and age-related disorders.

the redox equilibrium (**Figure 1**).

In this regard, ageing constitutes a natural, highly complex process that involves the progressive decay of several biological systems. Moreover, genetic and epigenetic heterogeneity introduces variation in the ageing process from one individual to another [2, 3]. In addition, an increased lifespan implies longer exposure to environmental pollutants that able to interact and modify different biological molecules, including DNA, not only affecting the functionality but also favouring the insurgence of several chronic degenerative disorders (http:// www.iarc.fr). Indeed, an altered DNA repair system, systemic and cellular redox imbalance related to mitochondrial dysfunction, sustained pro-inflammatory conditions and impaired immune system functionality are some of the several age-compromised homeostatic systems that can be at the root of pathological changes observed during ageing. Relevantly, and as occurs in other chronic degenerative processes, the breakdown of the homeostatic control and the verification of these alterations seem to depend not only on the impairment of one of the compromised systems but also on the concomitant failure of and crosstalk among others.

As an example, it can be noted that although a reduced methylation status has been recognised as a common condition of the aged genome, the promoter hypermethylation of some genes, with subsequent gene silencing, has also been described [2, 4–7]. The promoters of MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2), both part of the DNA mismatch repair system (MMR), have been reported to be hypermethylated due to arsenic exposure, suggesting an epigenetic-induced DNA MMR impairment that will increase the susceptibility of aged subjects to DNA damage [8]. Whether additional environmental pollutants or inner cellular metabolism end-products can modify the epigenetic control of such relevant mechanisms is an open question [9]. It is important to highlight that both MLH1 and MSH2 are related to the control of the impact that oxidative damage causes on DNA, and both have been observed to decrease during ageing [10]. Concomitantly, and in accordance with Harman's free radical theory [11], the redox balance has been well characterised in aged subjects, indicating that along with the age-related increased production of reactive oxygen and nitrogen species (ROS/RNS), mainly due to mitochondrial failure, the capability of different tissues, including the brain, to buffer ROS/RNS is diminished, as indicated by an increased oxidative status in older subjects [12, 13]. Indeed, the activity of the main ROS/RNS scavengers, including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx), has been demonstrated to decay with ageing, favouring ROS/ RNS-related damage, such as lipid peroxidation, protein denaturation and DNA mutations [14, 15]. Moreover, mitochondrial dysfunction, which also constitutes a key element in ageing, is considered one of the major components of the neurodegenerative process observed in both AD and PD. Importantly, beyond the energy impairment, mitochondrial alterations contribute significantly to the increased production of ROS/RNS, increasing the oxidative pressure on the redox equilibrium (**Figure 1**).

**1. Brief introduction to ageing**

46 Recent Advances in Neurodegeneration

Parkinson's disease (PD) [1].

Undoubtedly, the increased life expectancy of the global population constitutes a major achievement of the modern world. However, it has also opened a gate for the development of age-related conditions that are far from completely understood. In this regard, age-related diseases, particularly neurodegenerative disorders, currently constitute a public health focal point. Accordingly, in recent years, much attention has been focused on understanding both the physiology of ageing and the critical events driving pathological ageing with the subsequent development of different age-related disorders, such as Alzheimer's disease (AD) and

In this regard, ageing constitutes a natural, highly complex process that involves the progressive decay of several biological systems. Moreover, genetic and epigenetic heterogeneity introduces variation in the ageing process from one individual to another [2, 3]. In addition, an increased lifespan implies longer exposure to environmental pollutants that able to interact and modify different biological molecules, including DNA, not only affecting the functionality but also favouring the insurgence of several chronic degenerative disorders (http:// www.iarc.fr). Indeed, an altered DNA repair system, systemic and cellular redox imbalance related to mitochondrial dysfunction, sustained pro-inflammatory conditions and impaired immune system functionality are some of the several age-compromised homeostatic systems that can be at the root of pathological changes observed during ageing. Relevantly, and as occurs in other chronic degenerative processes, the breakdown of the homeostatic control and the verification of these alterations seem to depend not only on the impairment of one of the compromised systems but also on the concomitant failure of and crosstalk among others. As an example, it can be noted that although a reduced methylation status has been recognised as a common condition of the aged genome, the promoter hypermethylation of some genes, with subsequent gene silencing, has also been described [2, 4–7]. The promoters of MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2), both part of the DNA mismatch repair system (MMR), have been reported to be hypermethylated due to arsenic exposure, suggesting an epigenetic-induced DNA MMR impairment that will increase the susceptibility of aged subjects to DNA damage [8]. Whether additional environmental pollutants or inner cellular metabolism end-products can modify the epigenetic control of such relevant mechanisms is an open question [9]. It is important to highlight that both MLH1 and MSH2 are related to the control of the impact that oxidative damage causes on DNA, and both have been observed to decrease during ageing [10]. Concomitantly, and in accordance with Harman's free radical theory [11], the redox balance has been well characterised in aged subjects, indicating that along with the age-related increased production of reactive oxygen and nitrogen species (ROS/RNS), mainly due to mitochondrial failure, the capability of different tissues, including the brain, to buffer ROS/RNS is diminished, as indicated by an increased oxidative status in older subjects [12, 13]. Indeed, the activity of the main ROS/RNS scavengers, including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx), has been demonstrated to decay with ageing, favouring ROS/ RNS-related damage, such as lipid peroxidation, protein denaturation and DNA mutations [14, 15]. Moreover, mitochondrial dysfunction, which also constitutes a key element in ageing, On the other hand, it has been well established that chronic exposure to increased levels of prooxidant species leads to the concurrent activation of the immune system and triggering of the inflammatory cascade, both further sustained by the release of several pro-inflammatory mediators, such as several interleukins (IL-1, IL-6, IL-8) and interferon-γ (IFN-γ) [16–19]. Moreover, inflammation and the immune response both involve nuclear factor κb (NFκb), a common point that crosslinks both responses. While toll-like receptors (TLRs), which are activated by different subcellular molecular components (damage-associated molecular patterns, DAMPs), signal through NFκb to release several pro-inflammatory cytokines, leading to activation of the immune response, the very same NFκb constitutes an oxidative stress sensor, connecting the increased levels of ROS/RNS with activation of the inflammatory cascade [20, 21]. Additionally, it must be considered that immunocompetence is usually compromised in aged individuals, and several authors have shown that this decay is closely linked to the altered epigenetic control of several immune-related genes [22–24]. Altogether, this evidence suggests that the difference between "normal" and pathological ageing lies in the subtle equilibrium of different homeostatic

**Figure 1.** Homeostatic balance against pathological ageing, Alzheimer's disease (AD) and Parkinson's disease (PD). The delicate balance that sustains healthy ageing can be broken under several conditions. Environmental challenges, pathological processes, such as AD and PD, or ageing itself might introduce further pressure in different homeostatic systems, including the immune and redox systems. Moreover, the complex network of molecular alterations, organelle dysfunction and cellular signalling, among others, increases the difficulty of properly addressing the cloudy edge between healthy ageing, pathological ageing and age-related disorders.

systems that can become imbalanced with any additional external/internal stimulus, leading to failure of biological systems and the development of diverse pathological hallmarks.

In the following sections, we will summarise the most relevant aspects of AD and PD and the key elements of each pathophysiological process in the context of the delicate balance of an aged system.
