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Key Event Title
N/A, Neurodegeneration (updated)
|Level of Biological Organization|
Key Event Components
|abnormal neuron apoptosis||neuronal cell body||increased|
|Neuronal loss in central nervous system||neuron||increased|
Key Event Overview
AOPs Including This Key Event
Key Event Description
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 progressive loss of nerve structure and function, and neuronal loss by necrosis and/or apoptosis. The neuropathy of neurodegeneration not only results in the degradation and death of neurons, but also results in pathological changes to astrocytes, microglia and oligodendrocytes (Heneka et al., 2010; Rodríguez and Verkhratsky, 2011)
Neurodegeneration is a key aspect of a large number of human diseases that come under the umbrella of “neurodegenerative diseases" including Huntington's (HD), Alzheimer’s (AD) Multiple Sclerosis (MS), Dementia with Lewy Bodies (DLB), and Parkinson’s disease (PD). All of these conditions lead to progressive brain damage and neurodegeneration. Both dogs and cats can develop “cognitive dysfunction syndrome”, which is a homolog of AD in humans (Scuderi and Golini, 2021).
AD 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 progressive memory loss and inability to form new memories, leading to debilitating dementia and reduced lifespan.
PD is a “synucleinopathy” disease, a hallmark of which is the aggregation of misfolded alpha-synuclein and dopaminergic cell death. Symptoms begin with loss of sense of smell and constipation and progress to bradykinesia, rigidity, and resting tremor. Extensive analysis suggests that initial pathological changes occur in the olfactory and piriform cortex, followed by lesions and cell death in the medullary complex and substantia nigra pars compact, and from there spread to higher cortical regions such as the basal ganglia and motor cortex (Braak et al., 2003).
MS is an autoimmune disorder which is typically first diagnosed in early adulthood, and leads to progressive loss of myelination and degeneration of the underlying neurons and reduced life-expectancy (McGinley et al., 2021). Symptoms include problems with balance, mobility and gate, loss of vision, and cognitive decline.
Dementia with Lewy Bodies is the second-most common form of dementia after Alzheimer’s. Degeneration is marked by a build-up of tangles of the alpha-synuclein protein, termed “Lewy bodies”. Symptoms include decline in cognitive function, hallucinations, and can include motor symptoms present in PD.
Neurodegeneration can also develop from repeated traumatic brain injury (TBI), leading to chronic traumatic encephalopathy (CTE), a condition most associated with contact sports and military service. Repeated head impacts lead to a build-up of tau protein, resulting in progressive memory loss, confusion, tremor and movement disorders and cognitive decline.
It is important to note that affective symptoms such as depression and anxiety are present in virtually all neurodegenerative diseases.
Only an extremely small proportion (less than 5%) of neurodegenerative diseases are caused by genetic mutations (Narayan and Dragounov, 2017). Several observations suggest correlative links between environmental exposure and neurodegenerative diseases, but only few suggest causative links such as:
- A build up of toxic proteins in the brain (Ross and Poirier, 2004)
- A loss of mitochondrial function that leads to the oxidative stress and creation of neurotoxic molecules that trigger cell death (apoptotic, necrotic or autophagy) (Cobley et al., 2018)
- Downregulation in the levels and activities of neurotrophic factors (Rodrigues et al., 2014; Kazim and Iqbal, 2016; Machado et al., 2016; Dou et al., 2022)
- Variations in the activity of neural networks (Greicius and Kimmel, 2012)
- A cycle of chronic inflammation that leads to cell death (Block and Hong, 2005; Glass et al., 2010)
Protein aggregation: The correlation between neurodegenerative disease and protein aggregation in the brain has long been recognised, but a causal relationship has not been unequivocally established (Lansbury et al., 2006; Kumar et al., 2016).
In AD, PD, LBD and CTE, protein aggregation is a hallmark identifier.
In AD, abnormal intracellular accumulation of hyper phosphorylated tau proteins into “neurofibrillary tangles” occurs in conjunction with a build up of extracellular misfolded Amyloid-Beta (Aβ) which forms plaques that spread in a prion-like manner (Bloom, 2014). While there are clear genetic risk factors such as mutations to APP, PSEN1 and PSEN2, the majority of AD is deemed idiopathic (refs). It is unclear if the buildup of these toxic proteins is causal in neurodegeneration or merely an effect of other underlying processes, as several clinical trials which attempted to clear Aβ and tau have failed, and a recently approved antibody is not without controversy with respect to its effectiveness (Makin, 2018; Volloch and Rits, 2018; Tampi et al., 2021). Even if tau and Aβ are found to be causal components of neuronal loss in AD, underlying causes for misfolding and aggregation are still speculative, though recent work has identified potential viral infection vectors (Readhead et al., 2018).
A hallmark of CTE is abnormal aggregation of tau proteins (McKee et al., 2015).
In PD and LBD the normally pre-synaptic protein, alpha-synuclein, forms thread-like aggregates called Lewy neurites, or globular tangles, termed Lewy bodies. It is unclear if the neurodegeneration seen in synucleopathies is due to a prion-like progressive spread of aggregates from the brainstem to the cortex, or if the aggregation and spread is a knock-on effect from an as-yet unidentified causal source (Oliveira et al., 2021)
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 these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. 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, or specific interactions of disease-related proteins with mitochondria, hold great promise.
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's disease, Alzheimer disease and Parkinson disease (Zuccato and Cattaneo, 2009). 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 the aforementioned human diseases, with a view to ultimately influencing the clinical treatment of these conditions. Therefore BDNF treatment is being considered as a beneficial and feasible therapeutic approach in the clinic.
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 only temporarily able to overcome.
Chronic Inflammation: as with mitochondrial dysfunction, virtually all neurodegenerative conditions are marked by the presence of heightened levels of pro-inflammatory cytokines and activated microglia in the brain, often accompanied by a loss of phagocytotic function in microglia (Lull and Block, 2010; Tufekci et al., 2011; Heneka et al., 2015; Machado et al., 2016; Donat et al., 2017). In tauopathies and synucleinopathies, runaway inflammation has been linked to exacerbating neurodegeration by increasing oxidative stress and microglia-mediated inflammation (Cameron and Landreth, 2010; Odfalk et al., 2022). Clinical trials of anti-inflammatory agents have been largely unsuccessful in reversing cognitive decline associated with advanced AD, possibly due to being administered too late in the disease phase (Walker and Lue, 2005). Current anti-inflammatory treatment strategies are shifting to prodromomal disease phases with a variety of agents that target various aspects of inflammatory signaling, including conversion of microglia from a pro-inflammatory to phagocytotic/anti-inflammatory state (Gyengesi and Münch, 2020; Zhao et al., 2020; Lozupone et al., 2022)
Neurodegeneration in relation to COVID19
SARS-CoV-2 patients present elevated plasma levels of neurofilament light chain protein (NfL), which is a well-known biochemical indicator of neuronal injury (Kanberg et al., 2020). Postmortem brain autopsies demonstrate virus invasion to different brain regions, including the hypothalamus and olfactory bulb, accompanied by neural death and demyelination (Archie and Cucullo 2020; Heneka et al. 2020).
Autopsy results of patients with SARS showed ischemic neuronal damage and demyelination; viral RNA was detected in brain tissue, particularly accumulating in and around the hippocampus (Gu et al. 2005).
Brain magnetic resonance imaging (MRI) investigations in SARS-CoV-2 patients show multifocal hyperintense white matter lesions and cortical signal abnormalities (particularly in the medial temporal lobe) on fluid-attenuated inversion recovery (FLAIR), along with intracerebral hemorrhagic and microhemorrhagic lesions, and leptomeningeal enhancement (Kandemirli et al. 2020; Kremer et al. 2020; Mohammadi et al., 2020).
Moreover, eight COVID-19 patients with signs of encephalopathy had anti–SARS-CoV-2 antibodies in their CSF, and 4 patients had CSF positive for 14-3-3-protein suggesting ongoing neurodegeneration (Alexopoulos et al. 2020).
How It Is Measured or Detected
There are many aspects and hallmarks of neurodegeneration that can be detected in post-mortem analysis, however in human subjects, it is important to have reliable in vivo assessments.
The assays for measurements of necrotic or apoptotic cell death are described in the Key Event: Cell injury/Cell death
Fluoro-Jade B and C are commercially available in kit form and have been extensively used to stain degenerating neurons in fixed tissues and cell culture, regardless of specific insult or mechanism of cell death (Schmued et al., 2005). In particular, Fluoro-Jade C is highly resistant to fading and provides the highest signal-to-background ratio while supporting high resolution (Ehara and Ueda, 2009). In addition, Fluoro-Jade C can be used to identify both acutely and chronically degenerating neurons including distal dendrites and terminals.
A significant number of high throughput screening assays for a variety of degenerative and apoptotic biomarkers can also be used for drug screening (Linsley et al., 2019)
In vivo analyses
In vivo analysis methods can make use of both physiological assays for biomarker proteins in plasma and cerebrospinal fluid, as well as and neuroimaging to detect changes in blood flow, cortical thickness, and myelination. Proper detection may involve combining one or more of these techniques with cognitive and physical (motor) assessments.
Neurodegeneration can be indirectly detected by measuring disruptions in cortical network function through electroencephalography (EEG), though this technique may need to be combined with others for definitive diagnosis (McMackin et al., 2019).
Structural magnetic resonance imaging (MRI) of the brain can identify key atrophy patterns of neurodegeneration including enlarged ventricles, reduced cortical thickness. Additionally, it can identify hippocampal degeneration before the onset of symptoms. Regional patterns of loss in cortical thickness can be used diagnostically to identify different types of disorders (Young et al., 2020)
[18F]-2-Fluoro-2-deoxy-D-glucose (FDG) positron emission tracer (PET) scans measures glucose consumption in the brain. Glucose that is actively involved in metabolic function is trapped in tissue, thus measures of reduced FDG in tissue are indicative of neurodegeneration, and can be used to assess regional changes (Smailagic et al., 2015). Additionally, machine learning tools can be applied to measure loss of neuronal function correlated with cognitive assessment scores (Matthews et al., 2022). Three Aβ-specific tracers for PET scans have been approved for clinical use in the US, and show correlation with post-mortem histological markers of AD (Rowe et al., 2013).
Functional MRI has been used to detect degeneration via changes in resting state network function, and while research has highlighted some disease-specific changes, it is not in broad clinical use as a diagnostic tool (Chollet and Payoux, 2022)
Diffusion MRI methodologies, including Diffusion Tensor Imaging (DTI) neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI), and free-water imaging (FWI) detect mobility of water molecules and can be used to measure microstructural changes in white matter tracts that occur as a result of neurodegeneration (Kamagata et al., 2021)
Domain of Applicability
Neurodegeneration in humans
Neurodegeneration in humans is well-documented with several journals dedicated to this area of research (Young, 2009). A large number of human neuronal and glial cell lines have been developed to model and measure the impacts of neurodegenerative processes and to test potential treatments (Slanzi et al., 2020).
Though neurodegenerative diseases largely affect middle-aged to elderly humans (Hou et al., 2019), some forms of neurodegenration such as MS, CTE, and heritable disorders, can have earlier onsets. Even in AD, there is evidence that hallmark Aβ plaques may begin to form as early as 20 years of age, decades before any clinical symptoms appear (Braak and Braak, 1991). Similarly, by the time that motor symptoms are diagnosed in PD, an estimated that 31% of the dopaminergic neurons in the substantia nigra pars compacta have been lost, with an estimated 50-60% of the remaining neurons have damaged/degenerating axon terminals (Cheng et al., 2010).
In animals such as dogs, cats and non-human primates that spontaneously develop neurodegeneration, advanced age is a mediating factor.
WOE for lifestage: HIGH
Both male and female humans can suffer from neurodegeneration, however there are marked sex-differences in some of the diseases:
- Women are more likely than men to develop MS at a ratio of 3.2:1 (Orton et al., 2006)
- Women have a higher incidence and prevalence of AD, with greater risk conferred by having at least one alipoprotein E (APOE) allele (Seshadri et al., 1997), however men have a higher mortality in middle age from cardiovascular disease, which may skew risk profiles in old age (Chêne et al., 2015)
- Men have a 2-fold higher incidence and prevalence of PD, with greater impact on cognitive functions (Baldereschi et al., 2000; Oltra et al., 2022).
- In general, men have a higher prevalence of ALS in middle age at a 2:1 ratio over females, however, over the age of 70, that ratio shifts, and ALS becomes more prevalent in women (Manjaly et al., 2010)
WOE for sex : HIGH
WOE for humans: HIGH
Dogs and Cats: In elderly dogs and cats, “cognitive dysfunction syndrome” (CDS) is well-documented with both physical and behavioural changes that correlate with neurodegeneration (Scuderi and Golini, 2021). Laboratory beagles over 10 years of age have spontaneously developed Aβ plaques, with density increasing in proportion to advanced age (Russell et al., 1996). Magnetic resonance imaging studies have confirmed that dogs with CDS have greater atrophy in the forebrain and interthalamic regions which correlates with cognitive and behavioural changes (Su et al., 1998)
The brains of aged felines also have marked signs of neurodegeneration including hyperphosphorylated tau accumulation in neurons and oligodendrocytes, and a marked loss of neuronal cells in the hippocampus where both Aβ and tau deposits were present (Chambers et al., 2015). In cats, immunohistochemical analyses determined that Aβ begins to appear prior to the onset of “old age”, and in the same cortical regions as it does in humans (Sordo et al., 2021).
WOE for Canines: MODERATE
WOE for Felines: MODERATE
Non-human Primates (NHP): Aβ plaques and tau aggregation along with cortical atrophy and have been found in aged rhesus monkeys, cynomolgus monkeys, vervet monkeys, chimpanzees, tamarins and lemurs (Verdier et al., 2015). Age-related deficits in cognition in aged NHPs have been attributed to neurodegeneration (Verdier et al., 2015). Baboons begin to demonstrate cognitive decline at around 20 years of age, equivalent to a 60-yr-old human, and their brains have deposition of Aβ peptides (Ndung’u et al., 2012; Lizarraga et al., 2020).
WOE for NHP: MODERATE
Mice and Rats: The short life-span of mice and rats is posited as one possible reason why these animals have not been observed to develop neurodegenerative diseases in the wild. Admittedly, any rodent moderately debilitated by neurodegeneration would rapidly succumb to predators, and thus not survive, so lack of observation does not preclude the possibility. However, in lab-raised animals, mice and rats do not develop sporadic neurodegenerative diseases, nor do they exhibit signs of Aβ, tauopathies or synucleinopathies unless specifically transgenically modified or given neurotoxins. Even in transgenic mice, no model recapitulates the full spectrum of the human disease, and treatment models in rodents have generally failed in clinical trial results. Never-the-less, rodent models serve as important tools in the understanding of mechanistic processes involved in neurodegeneration (Dawson et al., 2018), and numerous in vivo and in vitro models based on rodents exist to study neurodegeneration in the context of both genetic and toxic mediators (Wong et al., 2002; Trancikova et al., 2011; Saez et al., 2013)
Regulatory Significance of the 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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COVID19-related references relevant to KE Neurodegeneration:
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