Ageing and neuronal vulnerability

Abstract

Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.

Figure 1. The who, where and when of neuronal death in age-related neurodegenerative disorders

a. Different neurodegenerative diseases such as ALS, Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD) affect different areas of the adult brain. Each starts in specific regions and later affects other regions. Even within these early affected regions a selective injury of neuron subclasses can be observed; for example the dopaminergic neurons in PD, the motor neurons in ALS, or the cholinergic and glutmatergic neurons in AD. b. Ages of disease onset of early-onset inherited forms and late-onset sporadic forms of neurodegenerative disorders. For further information visit: www.alz.org; www.parkinson.org; www.alsa.org; www.hdfoundation.org.

Figure 2. The nervous system may respond adaptively, or may succumb, to ageing

In aging and neurodegenerative diseases, neuronal death may be triggered by specific genetic mutations (for example mutations in huntingtin, presenilins, α-synuclein, and Cu/Zn-SOD) and/or environmental factors such as toxins or dietary components. Initiating factors promote cellular alterations including increased oxyradical production, perturbed energy and calcium homeostasis, and activation of apoptotic cascades. However, each factor cooperates with age-related increases in oxidative stress, metabolic compromise, DNA instability, and ion homeostasis dysregulation to disrupt neuronal integrity resulting in synaptic dysfunction and cell death. In addition, changes in glial cell homeostasis occur and contribute to inflammatory processes and white matter damage in neurodegenerative disorders. AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; Apo E2/3, apolipoprotein isoforms 2 and 3; APP, amyloid precursor protein; DJ-1, HD, Huntington's disease; PD, Parkinson's disease; PS1, 2, presenilins 1 and 2; SCA, spinocerebellar ataxia; SCNA, ; SOD1, superoxide dismutase 1; UCHL1, ubiquitin c-terminal hydrolase 1.

Figure 3. The sensitive synapse

Age- and disease-related stressors promote the activation of biochemical cascades that result in the ion dysregulation and energy depletion in synaptic terminals and neurites. One example is the stimulation of glutamate receptors which, under conditions of reduced energy availability or increased oxidative stress leads to Ca²⁺ influx into postsynaptic regions of dendrites. This in turn can trigger apoptosis (see figure 4). In addition, among other processes, ROS can induce lipid peroxidation resulting in the dysfunction of ion-motive ATPases and glucose and glutamate transporters. This leads to further ion dysregulation, energy depletion and excitotoxcity.

Figure 4. Once triggered, the death of neurons is programmed

Death signals activate intracellular cascades involving increased levels of ROS and Ca²⁺, production of Par-4 (prostate apoptosis response-4) and p53, and translocation of pro-apoptotic Bcl-2 family members (Bax and Bad) to the mitochondrial membrane. These events are followed by increased mitochondrial dysregulation and release of cytochrome c into the cytosol. Cytochrome c forms a complex with apoptotic protease-activating factor 1 (Apaf-1) and caspase-9. Activated caspase-9 cleaves and activates caspase-3 which, in turn cleaves protein substrates that effect changes in the plasma membrane, cytoskeleton and nucleus. Certain caspases (caspase-8, for example) can also be directly activated through death ligands and can act independently of mitochondrial changes. The process of apoptosis can be inhibited at different stages through anti-apoptotic mechanisms such as IAPs (inhibitor of apoptosis proteins) or Bcl2 and Bcl-xl. In general, cell fate is decided by a balance between survival factors and potentially harmful or destructive factors. atPKC, atypical protein kinase C; FADD, Fas-associated death domain protein.

Figure 5. Counteracting aging by stimulating beneficial cellular stress responses

Exercise, dietary restriction (DR) and cognitive stimulation have all been shown to protect neurons against dysfunction and death in animal models of neurodegenerative disorders. This occurs, in part, by induction of a mild stress response which induces the production of neurotrophic factors such as BDNF and GDNF, as well as protein chaperones such as HSP-70 and GRP-78. In addition, exercise and DR improve energy metabolism (increased insulin sensitivity) and cardiovascular health (decreased blood pressure and enhanced cardiovascular stress adaptation). This model is based largely on the results of studies in animals and, although such studies have been promising, it's not yet clear that exercise, DR and cognitive stimulation can protect against neurodegeneration in humans