- 1 Event Title
- 2 Key Event Overview
- 3 How this Key Event works
- 4 How it is Measured or Detected
- 5 Evidence Supporting Taxonomic Applicability
- 6 Regulatory Examples Using This Adverse Outcome
- 7 References
Key Event Overview
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AOPs Including This Key Event
Level of Biological Organization
How this Key Event works
The term neurodegeneration is a combination of two words - "neuro," referring to nerve cells and "degeneration," referring to progressive damage. The term "neurodegeneration" can be applied to several conditions that result in the loss of nerve structure and function including death of neurons. Neurodegeneration occurs in a large number of diseases that come under the umbrella of “neurodegenerative diseases" including, Huntington's, Alzheimer’s and Parkinson’s diseases. All of these conditions lead to progressive brain damage and neurodegeneration.
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions, with gross atrophy of the affected regions; symptoms include memory loss. Parkinson's disease (PD) results from the death of dopaminergic neurons in the midbrain substantia nigra pars compacta; symptoms include bradykinesia, rigidity, and resting tremor.
Several observations suggest correlative links between environmental exposure and neurodegenerative diseases, but only few suggest causative links:
In the brain, the cerebral cortex is highly sensitive to heavy metal exposure. This may be due to differential accumulation, such as observed following high concentrations of mercury (Hamilton et al, 2011), or to differential vulnerability. The hippocampus is the most affected structure following exposure to trimethyltin (TMT) (Dey et al, 1997; Fiedorowicz et al, 2001; Fiedorowicz et al, 2008; Robertson et al, 1987), or mercury exposure during the developmental period (Falluel-Morel et al, 2012). Pb2+ affects the hippocampus and the frontal cortex (Schneider et al, 2012). In these sensitive regions, a decrease of synapses or cellular loss is observed (Corvino et al, 2013; Dey et al, 1997). Changes in genes involved in the amyloid cascade related to Alzheimer’s disease were observed in the cortex of monkeys following Pb2+ exposure early in life (Zawia and Basha, 2005 ; Wu et al., 2008). In addition, aggregation of the amyloid peptide β was particularly enhanced in these monkeys after re-exposure to Pb2+ (Basha et al, 2005). These epigenetic modifications may be due to DNA methylation mediated in part through lead-induced dysregulation of methyltransferases (Schneider et al, 2013). The particular sensitivity of cortical areas to heavy metal exposure together with the increase of amyloid peptide deposition suggest a link between heavy metal exposure and Alzheimer’s pathology (Castoldi et al, 2008; Mutter et al, 2004) . Paraquat and rotenone induce specific lesions in the substantia nigra (Costello et al, 2009; Wu et al, 2013), suggesting that these toxicants may be causally associated with Parkinson’s disease.
Only an extremely small proportion (less than 5%) of neurodegenerative diseases are caused by genetic mutations. The remainders are thought to be caused by the following:
• A build up of toxic proteins in the brain (Lansbury et al., 2006; Majd et al., 2015; Zaltieri et al., 2015)
• A loss of mitochondrial function that leads to the oxidative stress and creation of neurotoxic molecules that trigger cell death (apoptotic, necrotic or autophagy) (Lin and Beal, 2006; Braun , 2012; Betarbet et al.,2000; Zhu and Chu, 2010)
• Changes in the levels and activities of neurotrophic factors (Zuccato and Cattaneo, 2009; Michalski et al., 2015)
• Variations in the activity of neural networks (Palop et al., 2006; Kann, 2015; Sala-Llonch et al., 2014).
Protein aggregation: the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized, but a causal relationship has not been unequivocally established (Lansbury et al., 2006). However, the causative link between mitochondrial dysfunction and its relationship to protein degradation and intracellular transport is well documented (Zaltieri et al., 2015). The dynamic nature of protein aggregation means that, despite progress towards understanding aggregation, its relationship to disease is difficult to determine in the laboratory. Nevertheless, drug candidates that inhibit aggregation are now being tested in the clinic. These have the potential to slow the progression of Alzheimer's disease, Parkinson's disease and related disorders and could, if administered pre-symptomatically, reduce the incidence of these disease (Gerard et al., 2010; McFarland and Okun, 2013).
Loss of mitochondrial function: many lines of evidence suggest that mitochondria have a central role in neurodegenerative diseases (Lin and Beal, 2006). Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Dysfunction of mitochondria induces oxidative stress, production of free radicals, calcium overload, and mutations in mitochondrial DNA that contribute to neurodegenerative diseases. In all major examples of neurodegenerative diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis (Zaltieri et al., 2015). Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation hold some promise (Navneet et al., 2012).
Decreased level of neurotrophic factors: decreased levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington disease, Alzheimer's disease and Parkinson's disease (Zuccato and Cattaneo, 2009; Michalski et al., 2015)). These studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic neurodegenerative human diseases, with a view to ultimately influencing the clinical treatment of these conditions. Therefore BDNF treatment is often used as a beneficial and feasible therapeutic approach in the clinic setting (Bai eta l., 2013; Nagahara and Tuszynski, 2011; Bradley 1999).
Variations in the activity of neural networks: Patients with various neurodegenerative disorders show remarkable fluctuations in neurological functions, even during the same day (Palop et al., 2006). These fluctuations cannot be caused by sudden loss or gain of nerve cells. Instead, it is likely that they reflect variations in the activity of neural networks and, perhaps, chronic intoxication by abnormal proteins that the brain is temporarily able to overcome. Variations in neuronal network activity are implicated in many brain diseases (Kann, 2015) as well as in aging (Sala-Llonch et al., 2014).
How it is Measured or Detected
The assays for measurements of necrotic or apoptotic cell death are described in the Key Event: Cell injury/Cell death
Recent neuropathological studies have shown that Fluoro-Jade, an anionic fluorescent dye, is a good marker of degenerating neurons. Fluoro-Jade and Fluoro-Jade B were found to stain all degenerating neurons, regardless of specific insult or mechanism of cell death (Schmued et al., 2005). More recently, Fluoro-Jade C was shown to be highly resistant to fading and compatible with virtually all histological processing and staining protocols (Schmued et al., 2005). In addition, Fluoro-Jade C is a good tool for detecting acutely and chronically degenerating neurons (Ehara and Ueda, 2009).
Evidence Supporting Taxonomic Applicability
The necrotic and apoptotic cell death pathways are quite well conserved throughout taxa (Blackstone and Green, 1999, Aravind et al., 2001). It has been widely suggested that apoptosis is also conserved in metazoans, although despite conservation of Bcl-2 proteins, APAF-1, and caspases there is no biochemical evidence of the existence of the mitochondrial pathway in either C. elegans or Drosophila apoptosis (Baum et al., 2007; Blackstone and Green, 1999).
Regulatory Examples Using This Adverse Outcome
Currently the four available OECD Test Guidelines (TGs) for neurotoxicity testing are entirely based on in vivo neurotoxicity studies: (1)Delayed Neurotoxicity of Organophosphorus Substances Following Acute Exposure (TG 418); (2) Delayed Neurotoxicity of Organophosphorus Substances: 28-day Repeated Dose Study (TG 419); (3) Neurotoxicity Study in Rodents (TG 424) involves daily oral dosing of rats for acute, subchronic, or chronic assessments (28 days, 90 days, or one year or longer); (4) Developmental Neurotoxicity (DNT) Study (TG 426) evaluates in utero and early postnatal effects by daily dosing of at least 60 pregnant rats from implantation through lactation. One of the endpoints required by all four of these OECD TGs is evaluation of neurodegeneration that, so far, is performed through in vivo neuropathological and histological studies. Therefore, neurodegeneration described in this AOP as a key event, has a regulatory relevance and could be performed using in vitro assays that allow a reliable evaluation of neurodegeneration using a large range of existing assays, specific for apoptosis, necrosis and autophagy ( see also KE Cell injury/Cell death).
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