Neurobiological effects of physical exercise

From Wikipedia, the free encyclopedia

Neurobiological effects of physical exercise
Exercise therapy – medical intervention
A woman engaging in aerobic exercise
ICD-9-CM	93.19
MeSH	D005081
LOINC	73986-2
eMedicine	324583

The neurobiological effects of physical exercise are numerous and involve a wide range of interrelated effects on brain structure, brain function, and cognition. A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent improvements in certain cognitive functions, healthy alterations in gene expression in the brain, and beneficial forms of neuroplasticity and behavioral plasticity; some of these long-term effects include: increased neuron growth, increased neurological activity (e.g., c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory. The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.

In healthy adults, aerobic exercise has been shown to induce transient effects on cognition after a single exercise session and persistent effects on cognition following regular exercise over the course of several months. People who regularly perform aerobic exercise (e.g., running, jogging, brisk walking, swimming, and cycling) have greater scores on neuropsychological function and performance tests that measure certain cognitive functions, such as attentional control, inhibitory control, cognitive flexibility, working memory updating and capacity, declarative memory, spatial memory, and information processing speed. The transient effects of exercise on cognition include improvements in most executive functions (e.g., attention, working memory, cognitive flexibility, inhibitory control, problem solving, and decision making) and information processing speed for a period of up to 2 hours after exercising.

Aerobic exercise induces short- and long-term effects on mood and emotional states by promoting positive affect, inhibiting negative affect, and decreasing the biological response to acute psychological stress. Over the short-term, aerobic exercise functions as both an antidepressant and euphoriant, whereas consistent exercise produces general improvements in mood and self-esteem.

Regular aerobic exercise improves symptoms associated with a variety of central nervous system disorders and may be used as an adjunct therapy for these disorders. There is clear evidence of exercise treatment efficacy for major depressive disorder and attention deficit hyperactivity disorder. The American Academy of Neurology's clinical practice guideline for mild cognitive impairment indicates that clinicians should recommend regular exercise (two times per week) to individuals who have been diagnosed with this condition. Reviews of clinical evidence also support the use of exercise as an adjunct therapy for certain neurodegenerative disorders, particularly Alzheimer’s disease and Parkinson's disease. Regular exercise is also associated with a lower risk of developing neurodegenerative disorders. A large body of preclinical evidence and emerging clinical evidence supports the use of exercise therapy for treating and preventing the development of drug addictions. Regular exercise has also been proposed as an adjunct therapy for brain cancers.

Long-term effects

Neuroplasticity

Neuroplasticity is the process by which neurons adapt to a disturbance over time, and most often occurs in response to repeated exposure to stimuli. Aerobic exercise increases the production of neurotrophic factors (e.g., BDNF, IGF-1, VEGF) which mediate improvements in cognitive functions and various forms of memory by promoting blood vessel formation in the brain, adult neurogenesis, and other forms of neuroplasticity. Consistent aerobic exercise over a period of several months induces clinically significant improvements in executive functions and increased gray matter volume in nearly all regions of the brain, with the most marked increases occurring in brain regions that give rise to executive functions. The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex, caudate nucleus, and hippocampus; less significant increases in gray matter volume occur in the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens. The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the dopamine and norepinephrine systems that give rise to cognitive control. Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory. Higher physical fitness scores, as measured by VO₂ max, are associated with better executive function, faster information processing speed, and greater gray matter volume of the hippocampus, caudate nucleus, and nucleus accumbens. Long-term aerobic exercise is also associated with persistent beneficial epigenetic changes that result in improved stress coping, improved cognitive function, and increased neuronal activity (c-Fos and BDNF signaling).

Structural growth

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter volume in nearly all regions of the brain, with more pronounced increases occurring in brain regions associated with memory processing, cognitive control, motor function, and reward; the most prominent gains in gray matter volume are seen in the prefrontal cortex, caudate nucleus, and hippocampus, which support cognitive control and memory processing, among other cognitive functions. Moreover, the left and right halves of the prefrontal cortex, the hippocampus, and the cingulate cortex appear to become more functionally interconnected in response to consistent aerobic exercise. Three reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that regularly engage in medium intensity exercise for several months. Other regions of the brain that demonstrate moderate or less significant gains in gray matter volume during neuroimaging include the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens.

Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood. Sedentary adults over age 55 show a 1–2% decline in hippocampal volume annually. A neuroimaging study with a sample of 120 adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one-year period. Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline. In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function. Aerobic exercise has also been shown to induce growth in the white matter tracts in the anterior corpus callosum, which normally shrink with age.

The various functions of the brain structures that show exercise-induced increases in gray matter volume include:

• Prefrontal and anterior cingulate cortices – required for the cognitive control of behavior, particularly: working memory, attentional control, decision-making, cognitive flexibility, social cognition, and inhibitory control of behavior; implicated in attention deficit hyperactivity disorder (ADHD) and addiction
• Nucleus accumbens – responsible for incentive salience ("wanting" or desire, the form of motivation associated with reward) and positive reinforcement; implicated in addiction
• Hippocampus – responsible for storage and consolidation of declarative memory and spatial memory; implicated in depression
• Cerebellum – responsible for motor coordination and motor learning
• Caudate nucleus – responsible for stimulus-response learning and inhibitory control; implicated in Parkinson's disease and ADHD
• Parietal cortex – responsible for sensory perception, working memory, and attention

Persistent effects on cognition

Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, regular exercise over a period of several months has been shown to persistently improve numerous executive functions and several forms of memory. In particular, consistent aerobic exercise has been shown to improve attentional control, information processing speed, cognitive flexibility (e.g., task switching), inhibitory control, working memory updating and capacity, declarative memory, and spatial memory. In healthy young and middle-aged adults, the effect sizes of improvements in cognitive function are largest for indices of executive functions and small to moderate for aspects of memory and information processing speed. It may be that in older adults, individuals benefit cognitively by taking part in both aerobic and resistance type exercise of at least moderate intensity. Individuals who have a sedentary lifestyle tend to have impaired executive functions relative to other more physically active non-exercisers. A reciprocal relationship between exercise and executive functions has also been noted: improvements in executive control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.

Mechanism of effects

BDNF signaling

One of the most significant effects of exercise on the brain is the increased synthesis and expression of BDNF, a neuropeptide and hormone, in the brain and periphery, resulting in increased signaling through its receptor tyrosine kinase, tropomyosin receptor kinase B (TrkB). Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain. Exercise-induced increases in brain BDNF signaling are associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory. Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair. Engaging in moderate-high intensity aerobic exercise such as running, swimming, and cycling increases BDNF biosynthesis through myokine signaling, resulting in up to a threefold increase in blood plasma and brain BDNF levels; exercise intensity is positively correlated with the magnitude of increased BDNF biosynthesis and expression. A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well.

IGF-1 signaling

IGF-1 is a peptide and neurotrophic factor that mediates some of the effects of growth hormone; IGF-1 elicits its physiological effects by binding to a specific receptor tyrosine kinase, the IGF-1 receptor, to control tissue growth and remodeling. In the brain, IGF-1 functions as a neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal survival. Physical activity is associated with increased levels of IGF-1 in blood serum, which is known to contribute to neuroplasticity in the brain due to its capacity to cross the blood–brain barrier and blood–cerebrospinal fluid barrier; consequently, one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis, while a second review characterized it as a factor which links "body fitness" with "brain fitness". The amount of IGF-1 released into blood plasma during exercise is positively correlated with exercise intensity and duration.

VEGF signaling

VEGF is a neurotrophic and angiogenic (i.e., blood vessel growth-promoting) signaling protein that binds to two receptor tyrosine kinases, VEGFR1 and VEGFR2, which are expressed in neurons and glial cells in the brain. Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons. Like BDNF and IGF-1, aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which subsequently crosses the blood–brain barrier and promotes neurogenesis and blood vessel formation in the central nervous system. Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.

Short-term effects

Transient effects on cognition

In addition to the persistent effects on cognition that result from several months of daily exercise, acute exercise (i.e., a single bout of exercise) has been shown to transiently improve a number of cognitive functions. Reviews and meta-analyses of research on the effects of acute exercise on cognition in healthy young and middle-aged adults have concluded that information processing speed and a number of executive functions – including attention, working memory, problem solving, cognitive flexibility, verbal fluency, decision making, and inhibitory control – all improve for a period of up to 2 hours post-exercise. A systematic review of studies conducted on children also suggested that some of the exercise-induced improvements in executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional control) only improve following consistent exercise on a regular basis. Other research has suggested performative enhancements during exercise, such as exercise-concurrent improvements in processing speed during visual working memory tasks.

Exercise-induced euphoria

Continuous exercise can produce a transient state of euphoria – a positively-valenced affective state involving the experience of pleasure and feelings of profound contentment, elation, and well-being – which is colloquially known as a "runner's high" in distance running or a "rower's high" in rowing. Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically phenethylamine (an endogenous psychostimulant), β-endorphin (an endogenous opioid), and anandamide (an endogenous cannabinoid).

Effects on neurochemistry

β-Phenylethylamine

β-Phenylethylamine, commonly referred to as phenethylamine, is a human trace amine and potent catecholaminergic and glutamatergic neuromodulator that has similar psychostimulant and euphoriant effects and a similar chemical structure to amphetamine. Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary β-phenylacetic acid, the primary metabolite of phenethylamine. Two reviews noted a study where the average 24 hour urinary β-phenylacetic acid concentration among participants following just 30 minutes of intense exercise increased by 77% relative to baseline concentrations in resting control subjects; the reviews suggest that phenethylamine synthesis sharply increases while an individual is exercising, during which time it is rapidly metabolized due to its short half-life of roughly 30 seconds. In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase (AADC) at approximately the same rate at which dopamine is produced.

In light of this observation, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both phenethylamine and amphetamine are potent euphoriants.

β-Endorphin

β-Endorphin (contracted from "endogenous morphine") is an endogenous opioid neuropeptide that binds to μ-opioid receptors, in turn producing euphoria and pain relief. A meta-analytic review found that exercise significantly increases the secretion of β-endorphin and that this secretion is correlated with improved mood states. Moderate intensity exercise produces the greatest increase in β-endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in β-endorphin synthesis. A review on β-endorphin and exercise noted that an individual's mood improves for the remainder of the day following physical exercise and that one's mood is positively correlated with overall daily physical activity level.

Anandamide

Anandamide is an endogenous cannabinoid and retrograde neurotransmitter that binds to cannabinoid receptors (primarily CB₁), in turn producing euphoria. It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~⁠70⁠–⁠80⁠% maximum heart rate). Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the blood–brain barrier and act within the central nervous system. Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis.

In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running.

Cortisol and the psychological stress response

Diagram of the hypothalamic–pituitary–adrenal axis

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors. Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis). Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control; however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has neurotoxic effects in the human brain. For example, chronic psychological stress decreases BDNF expression which has detrimental effects on hippocampal volume and can lead to depression.

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner; however, it does not result in long-term increases in cortisol production since this exercise-induced effect on cortisol is a response to transient negative energy balance. Individuals who have recently exercised exhibit improvements in stress coping behaviors. Aerobic exercise increases physical fitness and lowers neuroendocrine (i.e., HPA axis) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated heart rate response). Exercise also reverses stress-induced decreases in BDNF expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.

Glutamate and GABA

Glutamate, one of the most common neurochemicals in the brain, is an excitatory neurotransmitter involved in many aspects of brain function, including learning and memory. Based upon animal models, exercise appears to normalize the excessive levels of glutamate neurotransmission into the nucleus accumbens that occurs in drug addiction. A review of the effects of exercise on neurocardiac function in preclinical models noted that exercise-induced neuroplasticity of the rostral ventrolateral medulla (RVLM) has an inhibitory effect on glutamatergic neurotransmission in this region, in turn reducing sympathetic activity; the review hypothesized that this neuroplasticity in the RVLM is a mechanism by which regular exercise prevents inactivity-related cardiovascular disease.

Effects in children

Sibley and Etnier (2003) performed a meta-analysis that looked at the relationship between physical activity and cognitive performance in children. They reported a beneficial relationship in the categories of perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests, developmental level/academic readiness and other, with the exception of memory, that was found to be unrelated to physical activity. The correlation was strongest for the age ranges of 4–7 and 11–13 years. On the other hand, Chaddock and colleagues (2011) found results that contrasted Sibley and Etnier's meta-analysis. In their study, the hypothesis was that lower-fit children would perform poorly in executive control of memory and have smaller hippocampal volumes compared to higher-fit children. Instead of physical activity being unrelated to memory in children between 4 and 18 years of age, it may be that preadolescents of higher fitness have larger hippocampal volumes, than preadolescents of lower fitness. According to a previous study done by Chaddock and colleagues (Chaddock et al. 2010), a larger hippocampal volume would result in better executive control of memory. They concluded that hippocampal volume was positively associated with performance on relational memory tasks. Their findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain. In Best’s (2010) meta-analysis of the effect of activity on children’s executive function, there are two distinct experimental designs used to assess aerobic exercise on cognition. The first is chronic exercise, in which children are randomly assigned to a schedule of aerobic exercise over several weeks and later assessed at the end. The second is acute exercise, which examines the immediate changes in cognitive functioning after each session. The results of both suggest that aerobic exercise may briefly aid children’s executive function and also influence more lasting improvements to executive function. Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is. This area of study has been a focus for education boards that make decisions on whether physical education should be implemented in the school curriculum, how much time should be dedicated to physical education, and its impact on other academic subjects.

Another study found that sixth-graders who participated in vigorous physical activity at least three times a week had the highest scores compared to those who participated in moderate or no physical activity at all. The kids who participated in vigorous physical activity scored three points higher, on average, on their academic test, which consisted of math, science, English, and world studies.

Animal studies have also shown that exercise can impact brain development early on in life. Mice that had access to running wheels and other such exercise equipment had better neuronal growth in the neural systems involved in learning and memory. Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function. Some investigations have linked low levels of aerobic fitness in children with impaired executive function in older adults, but there is mounting evidence it may also be associated with a lack of selective attention, response inhibition, and interference control.

Effects on central nervous system disorders

Addiction

Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and psychostimulant addiction in particular. Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug-induced, addiction-related neuroplasticity. One review noted that exercise may prevent the development of drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system. Moreover, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D₂ (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density). Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction. As of 2016, more clinical research is still needed to understand the mechanisms and confirm the efficacy of exercise in drug addiction treatment and prevention.

Attention deficit hyperactivity disorder

Regular physical exercise, particularly aerobic exercise, is an effective add-on treatment for ADHD in children and adults, particularly when combined with stimulant medication (i.e., amphetamine or methylphenidate), although the best intensity and type of aerobic exercise for improving symptoms are not currently known. In particular, the long-term effects of regular aerobic exercise in ADHD individuals include better behavior and motor abilities, improved executive functions (including attention, inhibitory control, and planning, among other cognitive domains), faster information processing speed, and better memory. Parent-teacher ratings of behavioral and socio-emotional outcomes in response to regular aerobic exercise include: better overall function, reduced ADHD symptoms, better self-esteem, reduced levels of anxiety and depression, fewer somatic complaints, better academic and classroom behavior, and improved social behavior. Exercising while on stimulant medication augments the effect of stimulant medication on executive function. It is believed that these short-term effects of exercise are mediated by an increased abundance of synaptic dopamine and norepinephrine in the brain.

Major depressive disorder

A number of medical reviews have indicated that exercise has a marked and persistent antidepressant effect in humans, an effect believed to be mediated through enhanced BDNF signaling in the brain. Several systematic reviews have analyzed the potential for physical exercise in the treatment of depressive disorders. The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment (i.e., treatments that are used together) with antidepressant medication; the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression and mental illness in general. One systematic review noted that yoga may be effective in alleviating symptoms of prenatal depression. Another review asserted that evidence from clinical trials supports the efficacy of physical exercise as a treatment for depression over a 2–4 month period.

A 2015 review of clinical evidence which included a medical guideline for the treatment of depression with exercise noted that the available evidence on the effectiveness of exercise therapy for depression suffers from some limitations; nonetheless, it stated that there is clear evidence of efficacy for reducing symptoms of depression. The review also noted that patient characteristics, the type of depressive disorder, and the nature of the exercise program all affect the antidepressant properties of exercise therapy. A meta-analysis from July 2016 concluded that physical exercise improves overall quality of life in individuals with depression relative to controls.

Mild cognitive impairment

The American Academy of Neurology's January 2018 update of their clinical practice guideline for mild cognitive impairment states that clinicians should recommend regular exercise (two times per week) to individuals who have been diagnosed with this condition. This guidance is based upon a moderate amount of high-quality evidence which supports the efficacy of regular physical exercise (twice weekly over a 6-month period) for improving cognitive symptoms in individuals with mild cognitive impairment.

Neurodegenerative disorders

Alzheimer's disease

Alzheimer's Disease is a cortical neurodegenerative disorder and the most prevalent form of dementia, representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive function, behavioral abnormalities, and a reduced capacity to perform basic activities of daily life. Two meta-analytic systematic reviews of randomized controlled trials with durations of 3–12 months have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's disease. The reviews found beneficial effects of physical exercise on cognitive function, the rate of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's disease. One review suggested that, based upon transgenic mouse models, the cognitive effects of exercise on Alzheimer's disease may result from a reduction in the quantity of amyloid plaque.

The Caerphilly Prospective study followed 2,375 male subjects over 30 years and examined the association between healthy lifestyles and dementia, among other factors. Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment. A subsequent systematic review of longitudinal studies also found higher levels of physical activity to be associated with a reduction in the risk of dementia and cognitive decline; this review further asserted that increased physical activity appears to be causally related with these reduced risks.

Parkinson's disease

Parkinson's disease (PD) is a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait.

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way. A few studies reported seeing an improvement in brain health and cognitive function due to exercise. One particular study by Kramer and colleagues (1999) found that aerobic training improved executive control processes supported by frontal and prefrontal regions of the brain. These regions are responsible for the cognitive deficits in PD patients, however there was speculation that the difference in the neurochemical environment in the frontal lobes of PD patients may inhibit the benefit of aerobic exercise. Nocera and colleagues (2010) performed a case study based on this literature where they gave participants with early-to mid-staged PD, and the control group cognitive/language assessments with exercise regimens. Individuals performed 20 minutes of aerobic exercise three times a week for 8 weeks on a stationary exercise cycle. It was found that aerobic exercise improved several measures of cognitive function, providing evidence that such exercise regimens may be beneficial to patients with PD.

Neurotoxicity

From Wikipedia, the free encyclopedia

Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to substance – specifically, a neurotoxin – alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies (e.g., substances used in chemotherapy), recreational drug use, and exposure to heavy metals, pesticides, certain industrial cleaning solvents, and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction.

The term neurotoxicity implies the involvement of a neurotoxin; however, the term neurotoxic may be used more loosely to describe states that are known to cause physical brain damage, but where no specific neurotoxin has been identified.

The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances may impair neurocognitive performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is eliminated from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive drug use are beta amyloid (Aβ), glutamate, dopamine, and oxygen radicals. When present in high concentrations, they can lead to neurotoxicity and death (apoptosis). Some of the symptoms that result from cell death include loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of neurodegenerative diseases such as Alzheimer's disease (AD).

Neurotoxic agents

Beta amyloid

Aβ was found to cause neurotoxicity and cell death in the brain when present in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at the wrong locations, resulting in chains of different lengths that are unusable. Thus they are left in the brain until they are broken down, but if enough accumulate, they form plaques which are toxic to neurons. Aβ uses several routes in the central nervous system to cause cell death. An example is through the nicotinic acetylcholine receptor (nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of nicotine in the brain along with the MAP kinase, another signaling receptor, to cause cell death. Another chemical in the brain that Aβ regulates is JNK; this chemical halts the extracellular signal-regulated kinases (ERK) pathway, which normally functions as memory control in the brain. As a result, this memory favoring pathway is stopped, and the brain loses essential memory function. The loss of memory is a symptom of neurodegenerative disease, including AD. Another way Aβ causes cell death is through the phosphorylation of AKT; this occurs as the element phosphate is bound to several sites on the protein. This phosphorylation allows AKT to interact with BAD, a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKT/BAD complex, in turn stopping the action of the anti-apoptotic protein Bcl-2, which normally functions to stop cell death, causing accelerated neuron breakdown and the progression of AD.

Glutamate

Glutamate is a chemical found in the brain that poses a toxic threat to neurons when found in high concentrations. This concentration equilibrium is extremely delicate and is usually found in millimolar amounts extracellularly. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the glutamate transporters, which act like pumps to drain glutamate from the brain. This causes glutamate concentration to be several times higher in the blood than in the brain; in turn, the body must act to maintain equilibrium between the two concentrations by pumping the glutamate out of the bloodstream and into the neurons of the brain. In the event of a mutation, the glutamate transporters are unable to pump the glutamate back into the cells; thus a higher concentration accumulates at the glutamate receptors. This opens the ion channels, allowing calcium to enter the cell causing excitotoxicity. Glutamate results in cell death by turning on the N-methyl-D-aspartic acid receptors (NMDA); these receptors cause an increased release of calcium ions (Ca²⁺) into the cells. As a result, the increased concentration of Ca²⁺ directly increases the stress on mitochondria, resulting in excessive oxidative phosphorylation and production of reactive oxygen species (ROS) via the activation of nitric oxide synthase, ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron vulnerability to glutamate.

Oxygen radicals

The formation of oxygen radicals in the brain is achieved through the nitric oxide synthase (NOS) pathway. This reaction occurs as a response to an increase in the Ca²⁺ concentration inside a brain cell. This interaction between the Ca²⁺ and NOS results in the formation of the cofactor tetrahydrobiopterin (BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding nitric oxide (NO), which accumulates in the brain, increasing its oxidative stress. There are several ROS, including superoxide, hydrogen peroxide and hydroxyl, all of which lead to neurotoxicity. Naturally, the body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to break down the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress than other organs, due to its low oxidative capacity. Because neurons are characterized as postmitotic cells, meaning that they live with accumulated damage over the years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD.

Prognosis

The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.

Etymology and pronunciation

The word neurotoxicity (/ˌnʊəroʊtɒkˈsɪsɪti/) uses combining forms of neuro- + tox- + -icity, yielding "nervous tissue poisoning".

Prevention of dementia

From Wikipedia, the free encyclopedia

The aim of dementia prevention is to delay or prevent dementia. Dementia prevention is a global health priority and as such requires a global response. Recent initiatives include the establishment of the International Research Network on Dementia Prevention (IRNDP)which aims to link researchers in this field globally, and the establishment of the Global Dementia Observatory a web-based data knowledge and exchange platform, which will collate and disseminate key dementia data from members states. Although there is no cure for dementia currently, it is well established that modifiable risk factors influence both the likelihood of developing dementia and the age at which it is developed. Dementia can be prevented by reducing the risk factors for vascular disease (e.g. diabetes, high blood pressure, obesity, smoking, and physical inactivity) and depression. Livingstone et al. (2014) conclude that more than a third dementia cases are theoretically preventable.

Lifestyle

Mental activity

"Use it or lose it" might be applied to the brain when it comes to dementia. Intellectual activities help keep the mind in shape in later years. Activities such as reading, learning a new language, playing cards and board games and playing a musical instrument can postpone the onset and slow the progression of both Alzheimer's and vascular dementia. The risk decrease is proportional to frequency of activity, with slower cognitive decline being associated with both late-life and early-life increased cognitive activity.

Apart from spare time activities, a mentally demanding job may prevent dementia, especially during the thirties, forties and fifties.

Mental activity may help to prevent dementia by building up a "brain reserve": additional connections between neurons are created which are more resistant to the deterioration seen in dementia.

Physical activity

Since vascular dementia is the second most common form of dementia (after Alzheimer's disease), reducing the risk of cerebrovascular disease also reduces the risk of dementia. Thus, physical exercise, having good blood cholesterol, healthy body weight and blood pressure lowers the risk of developing dementia. An active lifestyle can almost halve the risk compared to a sedentary one.

Results of one meta-analysis, which investigated the relationship between physical activity and risk of cognitive decline in people without dementia, showed exercise had a significant and consistent protective effect against cognitive decline, with high levels of physical activity being most protective. Another meta-analysis showed that not only did aerobic exercise reduce the risk of dementia but it may also slow cognitive decline in those with dementia.

The effect of physical activity is not limited to vascular effects. Physical activity can give rise to new neurons in the brain, as well as releasing a substance that can protect them. The protein known as brain-derived neurotrophic factor (BDNF) is known to be important in the development, survival and plasticity of neurons. Regular exercise can boost BDNF levels by 2–3 times.

Diet

Obesity increases the risk of any dementia and Alzheimer's disease in particular. The effect of alcohol on the risk of dementia is a J curve: high alcohol consumption increases the risk of dementia while low alcohol consumption may be protective. However, low alcohol consumption may not protect against vascular dementia and overall cognitive decline. Moderate alcohol consumption can possibly reduce the risk of vascular disease and dementia because it can increase blood levels of HDL cholesterol and weakens blood-clotting agents such as fibrinogen, which offers some protection against heart attacks and small subclinical strokes that together can ultimately damage the brain.

The effects of omega-3 fatty acid in the prevention of dementia is uncertain. Vegetables and nuts may be of benefit, because of their high content of polyunsaturated fats. Non-fish meat, on the other hand, increases the risk of Alzheimer's, because of its high content of saturated fat. However, consumption of fish should be limited due to concerns over mercury poisoning, which could exacerbate the symptoms of dementia. 

Niacin (vitamin B₃) is also believed to prevent dementia as research shows those who have the highest levels of niacin in their blood, are believed to have the lowest risk of developing dementia or having cognitive decline. Niacin is involved with DNA synthesis and repair and also neural cell signaling, it improves circulation and reduces cholesterol levels. In order for niacin to have a positive effect on the brain, it is recommended that patients have 100 to 300 mg per day.

There is evidence for an association between cognitive decline, homocysteine (Hcy) status, and vitamin B status relating especially to B12 and also to vitamins B6 and B9. In particular, deficiency of vitamin B12 and/or of folate can cause an increase in Hcy plasma levels, which in turn leads to toxic effects on the vascular and nervous systems.

Vitamin D deficiency correlates with cognitive impairment and dementia; however, the value of vitamin D substitution in cognitive impairment remains doubtful.

Sleep pattern

More than nine hours of sleep per day (including daytime napping) may be associated with an increased risk of dementia. Lack of sleep may also increase risk of dementia by increasing beta-amyloid deposition.

Personality and Mental Health

Being neurotic increases the risk of developing Alzheimer's, a type of dementia. Neuroticism is associated with increased brain atrophy and cognitive impairment in life, while conscientiousness has a protective effect by preventing brain atrophy.

Depression

Depressive symptoms can be a part of the clinical presentation of dementia, leading to debate as to whether depression is a cause or a symptom of dementia. The evidence remains unclear. However, Livingstone et al. (2014) report that it is "biologically plausible" that depression increases the risk of dementia. There is some evidence that late-life depression increases the risk of dementia however suggesting treating depression in mid-life might delay or prevent dementia.

Medication

Hypertension

Some studies say Alzheimer's and other dementias may be caused by high blood pressure, since it can cause blood vessel damage through constriction. The etiology of vascular dementia includes hypertension, and thus, lowering blood pressure with antihypertensives may have a positive effect in the prevention of dementia, just as physical activity.

However, one study failed to demonstrate a link between high blood pressure and developing dementia. The study, published in the Lancet Neurology journal of July 2008, found that blood pressure lowering medication did not reduce the incidence of dementia to a statistically significant degree. A prospective meta-analysis of the data from this study with other studies suggested that further research might be warranted.

A study of participants in the Leisure World Cohort Study and The 90+ Study showed that people whose high blood pressure began in their 80s might be less likely to develop dementia than people who did not have high blood pressure.

While the results of studies are somewhat inconsistent, it has been recommended that hypertension in mid-life (45–65 years) and older age (65+ years) should be actively treated to reduce the risk of dementia.

Anti-diabetic drugs

Diabetes mellitus is a risk factor for vascular dementia, and is thus the risk is lowered with anti-diabetic drugs.

Besides, Rosiglitazone (Avandia) improves memory and thinking ability for people with mild Alzheimer's disease. The mechanism of the effect may be the ability of the drug to reduce insulin resistance. Thus, less insulin needs to be released to achieve its metabolic effects. Insulin in the bloodstream is a trigger of amyloid beta-production, so decreased insulin levels decrease the level of amyloid beta. This leads to less formation of amyloid plaques seen in Alzheimer's disease.

Steroid hormones

Estrogen may also help in the prevention of dementia but cannot help when dementia is already present and when cognitive function is already impaired. It increases cerebral blood flow and is an anti-inflammatory agent, enhancing activity at the neuronal synapses in the brain. It may also help to increase brain activation in regions that are affected by dementia which is mainly the hippocampus region. Recent evidence on the effects of estrogen do not allow for an unambiguous recommendation for estrogen supplementation and they indicate that the timing of estrogen supplementation may be important, with early postmenopausal use being preferable over its use later in life.

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the risk of developing Alzheimer's and Parkinson's diseases. The length of time needed to prevent dementia varies, but in most studies it is usually between 2 and 10 years. Research has also shown that it must be used in clinically relevant dosages and that so called "baby aspirin" doses are ineffective at treating dementia.

Alzheimer's disease causes inflammation in the neurons by its deposits of amyloid beta peptides and neurofibrillary tangles. These deposits irritate the body by causing a release of e.g. cytokines and acute phase proteins, leading to inflammation. When these substances accumulate over years they contribute to the effects of Alzheimer's. NSAIDs inhibit the formation of such inflammatory substances, and prevent the deteriorating effects.

Vaccine

There is as yet no vaccine against dementia. It has been theorized that a vaccine could activate the body's own immune system to combat the beta amyloid plaques in Alzheimer's disease. One problem to overcome is overreaction from the immune system, leading to encephalitis.

Neurodegeneration

From Wikipedia, the free encyclopedia

Neurodegeneration
Para-sagittal MRI of the head in a patient with benign familial macrocephaly.
Specialty	Neurology, Psychiatry

Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases – including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease – occur as a result of neurodegenerative processes. Such diseases are incurable, resulting in progressive degeneration and/or death of neuron cells. As research progresses, many similarities appear that relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic.

Risk factor

The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging. Many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease. One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age. It has been proposed that DNA damage accumulation provides the underlying causative link between aging and neurodegenerative disease.

Mechanisms

Genetics

Many neurodegenerative diseases are caused by genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG encodes for the amino acid glutamine. A repeat of CAG results in a polyglutamine (polyQ) tract. Diseases showing this are known as polyglutamine diseases.

• Polyglutamine: A repeat in this causes dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins. PolyQ studies often use a variety of animal models because there is such a clearly defined trigger – repeat expansion. Extensive research has been done using the models of nematode (C. elegans), and fruit fly (Drosophila), mice, and non-human primates. Mammalian data is often needed for FDA approval of drugs, which means that the bulk of the research is done using mice. Using data from the other animals (C. elegans and Drosophila primarily) is often a precursor to finding the equivalent mammalian gene.
  • Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract. Two examples are Huntington's disease and the spinocerebellar ataxias. For a complete list, see the table under Polyglutamine (PolyQ) Diseases in the article Trinucleotide repeat disorder. While polyglutamine-repeat diseases encompass many different neurodegenerative disorders, there are many more it does not apply to. The genetics behind each disease are different and often unknown.

Protein misfolding

Several neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins.

• alpha-synuclein: can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer's disease.
• tau: hyperphosphorylated tau protein is the main component of neurofibrillary tangles in Alzheimer's disease.
• beta amyloid: the major component of senile plaques in Alzheimer's disease.
• prion: main component of prion diseases and transmissible spongiform encephalopathies.

Intracellular mechanisms

Protein degradation pathways

Parkinson's disease and Huntington's disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as proteinopathies, and they are primarily caused by aggregates in the following structures:

• cytosol, e.g. Parkinson's & Huntington's
• nucleus, e.g. Spinocerebellar ataxia type 1 (SCA1)
• endoplasmic reticulum (ER), (as seen with neuroserpin mutations that cause familial encephalopathy with neuroserpin inclusion bodies)
• extracellularly excreted proteins, amyloid-β in Alzheimer's disease

There are two main avenues eukaryotic cells use to remove troublesome proteins or organelles:

• ubiquitin–proteasome: protein ubiquitin along with enzymes is key for the degradation of many proteins that cause proteinopathies including polyQ expansions and alpha-synucleins. Research indicates proteasome enzymes may not be able to correctly cleave these irregular proteins, which could possibly result in a more toxic species. This is the primary route cells use to degrade proteins.
  • Decreased proteasome activity is consistent with models in which intracellular protein aggregates form. It is still unknown whether or not these aggregates are a cause or a result of neurodegeneration.
• autophagy–lysosome pathways: a form of programmed cell death (PCD), this becomes the favorable route when a protein is aggregate-prone meaning it is a poor proteasome substrate. This can be split into two forms of autophagy: macroautophagy and chaperone-mediated autophagy (CMA).
  • macroautophagy is involved with nutrient recycling of macromolecules under conditions of starvation, certain apoptotic pathways, and if absent, leads to the formation of ubiquinated inclusions. Experiments in mice with neuronally confined macroautophagy-gene knockouts develop intraneuronal aggregates leading to neurodegeneration.
  • chaperone-mediated autophagy defects may also lead to neurodegeneration. Research has shown that mutant proteins bind to the CMA-pathway receptors on lysosomal membrane and in doing so block their own degradation as well as the degradation of other substrates.

Membrane damage

Damage to the membranes of organelles by monomeric or oligomeric proteins could also contribute to these diseases. Alpha-synuclein can damage membranes by inducing membrane curvature, and cause extensive tubulation and vesiculation when incubated with artificial phospholipid vesicles. The tubes formed from these lipid vesicles consist of both micellar as well as bilayer tubes. Extensive induction of membrane curvature is deleterious to the cell and would eventually lead to cell death.Apart from tubular structures, alpha-synuclein can also form lipoprotein nanoparticles similar to apolipoproteins.

Mitochondrial dysfunction

The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial intermembrane space (IMS). Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity. ROS concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and glutathione peroxidase. Over production of ROS (oxidative stress) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions.

There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis.

Neurons are particularly vulnerable to oxidative damage due to their strong metabolic activity associated with high transcription levels, high oxygen consumption, and weak antioxidant defense.

DNA Damage

The brain metabolizes as much as a fifth of consumed oxygen, and reactive oxygen species produced by oxidative metabolism are a major source of DNA damage in the brain. Damage to a cell’s DNA is particularly harmful because DNA is the blueprint for protein production and unlike other molecules it cannot simply be replaced by re-synthesis. The vulnerability of post-mitotic neurons to DNA damage (such as oxidative lesions or certain types of DNA strand breaks), coupled with a gradual decline in the activities of repair mechanisms, could lead to accumulation of DNA damage with age and contribute to brain aging and neurodegeneration. DNA single-strand breaks are common and are associated with the neurodegenerative disease ataxia-oculomotor apraxia. Increased oxidative DNA damage in the brain is associated with Alzheimer’s disease and Parkinson’s disease. Defective DNA repair has been linked to neurodegenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Cockayne syndrome, Parkinson’s disease and xeroderma pigmentosum.

Axonal transport

Axonal swelling and spheroids have been observed in many different neurodegenerative diseases. This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. Axonal transport can be disrupted by a variety of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes, and mitochondria. When axonal transport is severely disrupted a degenerative pathway known as Wallerian-like degeneration is often triggered.

Programmed cell death

Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program. This process can be activated in neurodegenerative diseases including Parkinson's disease, amytrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. There are, however, situations in which these mediated pathways are artificially stimulated due to injury or disease.

Apoptosis (type I)

Apoptosis is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death.

• Extrinsic apoptotic pathways: Occur when factors outside the cell activate cell surface death receptors (e.g., Fas) that result in the activation of caspases-8 or -10.
• Intrinsic apoptotic pathways: Result from mitochondrial release of cytochrome c or endoplasmic reticulum malfunctions, each leading to the activation of caspase-9. The nucleus and Golgi apparatus are other organelles that have damage sensors, which can lead the cells down apoptotic pathways.

Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation.

Autophagic (type II)

Autophagy is essentially a form of intracellular phagocytosis in which a cell actively consumes damaged organelles or misfolded proteins by encapsulating them into an autophagosome, which fuses with a lysosome to destroy the contents of the autophagosome. Many neurodegenerative diseases show unusual protein aggregates. This could potentially be a result of underlying autophagic defect common to multiple neurodegenerative diseases. It is important to note that this is a hypothesis, and more research must be done.

Cytoplasmic (type III)

The final and least understood PCD mechanism is through non-apoptotic processes. These fall under Type III, or cytoplasmic cell death. Many other forms of PCD are observed but not fully understood or accepted by the scientific community. For example, PCD might be caused by trophotoxicity, or hyperactivation of trophic factor receptors. In addition to this, other cytotoxins that induce PCD at low concentrations act to cause necrosis, or aponecrosis – the combination of apoptosis and necrosis, when in higher concentrations. It is still unclear exactly what combination of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis.

PCD

In the above-mentioned neurodegenerative diseases, PCD may be pathogenic. In order to identify the potential of neuroprotective targets in PCD machinery, there were experimental models conducted on these neurodegenerative diseases. These studies showed that the expression of certain components have been altered by genetic and pharmacological means. Expression of PCD molecular components are said to be controlled by gene and antisense therapy, but this needs further research. Pharmacological approaches involve inhibitors of caspase activity, and caspase inhibition might delay cell death in the different experimental models.

Transglutaminase

Transglutaminases are human enzymes ubiquitously present in the human body and in the brain in particular.

The main function of transglutaminases is bind proteins and peptides intra- and intermolecularly, by a type of covalent bonds termed isopeptide bonds, in a reaction termed transamidation or crosslinking.

Transglutaminase binding of these proteins and peptides make them clump together. The resulting structures are turned extremely resistant to chemical and mechanical disruption.

Most relevant human neurodegenerative diseases share the property of having abnormal structures made up of proteins and peptides.

Each of these neurodegenerative disesases have one (or several) specific main protein or peptide. In Alzheimer's disease, these are amyloid-beta and tau. In Parkinson’s disease, it is alpha-synuclein. In Huntington’s disease, it is huntingtin.

Transglutaminase substrates: Amyloid-beta, tau, alpha-synuclein and huntingtin have been proved to be substrates of transglutaminases in vitro or in vivo, that is, they can be bonded by trasglutaminases by covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.

Transglutaminase augmented expression: It has been proved that in these neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease) the expression of the transglutaminase enzyme is increased.

Presence of isopeptide bonds in these structures: The presence of isopeptide bonds (the result of the transglutaminase reaction) have been detected in the abnormal structures that are characteristic of these neurodegenerative diseases.

Co-localization: Co-localization of transglutaminase mediated isopeptide bonds with these abnormal structures has been detected in the autopsy of brains of patients with these diseases.

Specific disorders

Alzheimer's disease

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.

Alzheimer's disease has been hypothesized to be a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.

Parkinson's disease

Parkinson's disease is the second most common neurodegenerative disorder and manifests as bradykinesia, rigidity, resting tremor and posture instability. The crude prevalence rate of PD has been reported to range from 15 per 100,000 to 12,500 per 100,000, and the incidence of PD from 15 per 100,000 to 328 per 100,000, with the disease being less common in Asian countries. Parkinson's disease is a degenerative disorder of the central nervous system. It results from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. The following paragraph is an excerpt from the Pathophysiology section of the article Parkinson's disease.

The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteasome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles – the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.

Recent research suggests that impaired axonal transport of alpha-synuclein leads to its accumulation in the Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons. Membrane damage by alpha-synuclein could be another Parkinson's disease mechanism.

The main known risk factor is age. Susceptibility genes including α-synuclein, leucine-rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor.

Huntington's disease

The following paragraph is an excerpt from the Mechanism section of the article Huntington's disease.

HD causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder, notably chorea.

Mutant Huntingtin is an aggregate-prone protein. During the cells' natural clearance process, these proteins are retrogradely transported to the cell body for destruction by lysosomes. It is a possibility that these mutant protein aggregates damage the retrograde transport of important cargoes such as BDNF by damaging molecular motors as well as microtubules.

Amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a disease in which motor neurons are selectively targeted for degeneration. In 1993, missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in subsets of patients with familial ALS. This discovery led researchers to focus on unlocking the mechanisms for SOD1-mediated diseases. However, the pathogenic mechanism underlying SOD1 mutant toxicity has yet to be resolved. More recently, TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (C9orf72) is thought to be the most common known cause of sporadic ALS. 

Recent independent research by Nagai et al. and Di Giorgio et al. provide in vitro evidence that the primary cellular sites where SOD1 mutations act are located on astrocytes. Astrocytes then cause the toxic effects on the motor neurons. The specific mechanism of toxicity still needs to be investigated, but the findings are significant because they implicate cells other than neuron cells in neurodegeneration.

Therapeutics

The process of neurodegeneration is not well understood, so the diseases that stem from it have, as yet, no cures. In the search for effective treatments (as opposed to palliative care), investigators employ animal models of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon (Medivation). This drug is in phase III clinical trials for use in Alzheimer's disease, and also recently finished phase II clinical trials for use in Huntington's disease. In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug Dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease. With CONCERT, the remaining Pfizer and Medivation Phase III trial for Dimebon (latrepirdine) in Alzheimer's disease failed in 2012, effectively ending the development in this indication.

In another experiment using a rat model of Alzheimer's disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus amyloid-beta 25–35. This suggests that there could be therapeutic value to PRP-1.

Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.

The goal of immunotherapy is to enhance aspects of the immune system. Both active and passive vaccinations have been proposed for Alzheimer's disease and other conditions; however, more research must be done to prove safety and efficacy in humans.