• Author
  • Departments of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
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Neurodegeneration

Synonyms

Neuronal cell deterioration; Neuronal cell death

Definition

Neurodegeneration refers to the processes whereby damaged neuronal cells deteriorate or degenerate and eventually die.

Since the body's ability to replace lost neurons (i.e., such as via neurogenesis) is quite limited when compared to many nonneuronal cells, degenerative processes affecting neurons can be quite devastating.

Basic Mechanisms

The basic mechanisms underlying the neuronal cell degeneration and death observed in the neurologic disorders as diverse as Alzheimer's disease and stroke have not been fully elucidated. However, a number of distinct factors and processes clearly contribute to neurodegeneration including increased oxidative stress and free radical damage, impaired mitochondrial function, excitotoxicity, immunologic and inflammatory mechanisms, impaired trophic factor support, and altered cell signaling. In the process of neuronal degeneration, cells eventually die as a result of one of two processes, apoptosis or necrosis.

Necrosis

Necrosis (sometimes referred to as cellular dissolution) occurs as a pathological response to cell injury most commonly resulting from trauma, ischemia, hypoxia, neurotoxins, or infection. Necrosis occurs when a cell is too severely damaged for the orderly energy‐dependent process of apoptosis (see below) to occur. Following one or more of the insults listed above, neuronal degeneration or death occurs in groups of contiguous cells in a localized region and the initiation of inflammatory processes can be clearly observed in tissue sections [1]. In the process of necrosis, an initial swelling of the cell occurs (Fig. 1 and Table 1), little or no chromatin condensation is evident, mitochondria and other organelles swell and rupture, the plasma membrane lyses, and spillage of the cellular contents into the extracellular space follows. A general inflammatory response is then triggered and macrophages attack and phagocytize the cellular debris.
Neurodegeneration. Figure 1 Illustration of the major cellular changes observed in neuronal necrosis. A normal neuronal cell (a) when exposed to an insult (e.g., trauma, ischemia, hypoxia, neurotoxins, infection, etc.) initially swells (b), mitochondria and other organelles swell and rupture, the plasma membrane lyses (c), and spillage of the cellular contents into the extracellular space follows. A general inflammatory response (d) is then triggered and macrophages attack and phagocytize the cellular debris.
Neurodegeneration. Table 1 Comparison of necrosis and apoptosis

Necrosis

Apoptosis

Cellular swelling

Cellular shrinkage

Nuclear and cellular pyknosis

Little or no chromatin condensation

Chromatin condensation

Rupture of organelles and plasma membrane

Organelles and plasma membrane not usually ruptured

Release of cytoplasmic contents and inflammation

Release of cytoplasmic contents and inflammation not usually present

Random DNA degradation

DNA fragmentation

Caspases not involved

Activation of caspases

Cytoplasmic blebbing

Formation of apoptotic bodies which are engulfed and cleared by phagocytes

Apoptosis

Neuronal apoptosis (old Greek term for dropping off, like leaves in the fall) is triggered by a number of factors including lipid peroxidation (and membrane damage) induced by reactive oxygen species, genetic mutation, or DNA damage (or degradation) resulting from radiation or other destructive agents. A loss of trophic factor support, as well as some of the same factors that induce necrosis (see above) can also initiate apoptotic processes. Cell death by apoptosis also occurs extensively during the development of the mammalian nervous system and is required for the formation of appropriate connections between neurons and their targets. The processes involved in apoptosis differ from necrosis (Table 1) in several important details, most notably, that neuronal death with apoptosis usually involves individual cells that are phagocytized before they can release their cytoplasmic contents and induce an inflammatory response in adjacent tissues, and phagocytes are able to recognize dying or degenerating cells by their expression of death related cell surface epitopes. Furthermore, mitochondria are preserved until the late stages of apoptosis, whereas they swell and disintegrate early in necrosis. Figure 2 illustrates the major cellular changes observed in neuronal apoptosis. A normal neuronal cell (a) when exposed to specific triggers (e.g., lipid peroxidation, genetic mutation, DNA damage, excitotoxic injury, etc.) initially shrinks, chromatin becomes pyknotic (more dense) and condenses, then migrates to the nuclear membrane, DNA fragmentation and degradation occurs, and several organelles disappear (e.g., Golgi apparatus, endoplasmic reticulum). Afterwards, blebbing of the plasma membrane occurs (c), the cell then fragments into small apoptotic bodies that are subsequently phagocytosed and digested (d) without triggering inflammation.
Neurodegeneration. Figure 2 Illustration of the major cellular changes observed in neuronal apoptosis. A normal neuronal cell (a) when exposed to specific triggers (e.g., lipid peroxidation, genetic mutation, DNA damage, excitotoxic injury, etc.) initially shrinks, chromatin becomes pyknotic and condenses, then migrates to the nuclear membrane, DNA fragmentation and degradation occurs, and several organelles disappear. Afterwards, blebbing of the plasma membrane occurs (c), the cell then fragments into small apoptotic bodies that are subsequently phagocytosed and digested (d) without triggering inflammation.

As mentioned above, neuronal apoptosis serves a number of important roles in normal brain development and is a key mechanism by which defective or damaged neurons are removed from the brain. However, in a number of brain disorders including Alzheimer's disease, Dementia with Lewy bodies, and Parkinson's disease, inappropriate apoptosis may occur leading to accelerated neuronal loss and progressive disease symptoms. On the other hand in neural tumor cells, such as neuroblastoma and medulloblastoma cells, apoptotic pathways may be disabled and the cells become resistant to chemotherapeutic drugs that kill cancer cells by inducing apoptosis. Neuroblastoma and medulloblastoma are important pediatric solid tumors that arise in the sympathetic neuron lineage and cerebellum, respectively. Apoptosis may be accelerated or retarded by a variety of hormones, metabolic byproducts, electrolytes, and other endogenous substances. For example, altered serum levels of thyroid hormone or ammonia, altered plasma or extracellular levels of excitatory amino acids such as glutamate and aspartate, imbalances of calcium and other electrolytes, and lactic acidosis are all known to initiate or modify apoptotic processes. Apoptosis is also influenced by synaptic communication in both the central and peripheral nervous systems. For example, in transsynaptic degeneration, neurons deteriorate and often undergo apoptosis if they fail to be innervated (from the afferent side) due to the loss of presynaptic neurons. This process has been observed in the lateral genicular body after optic nerve lesions and in the inferior olivary nucleus after destruction of the central tegmental tract. Efferent, motor neurons degenerate if they fail to match with target muscle fibers or their muscle targets are lost, such as after amputation of a limb.

There is an increasing body of evidence that supports an apoptosis-necrosis cell death continuum. In this continuum, neuronal death can result from varying contributions of coexisting apoptotic and necrotic mechanisms [2]. Therefore the distinct designations above (necrosis vs. apoptosis) are beginning to blur. Table 1 provides an overview of the major differences between necrosis and apoptosis.

Regulation of Apoptosis

Apoptosis is regulated by a complex molecular cascade that controls the activation of a family of cysteine proteases known as caspase proteins (caspases 1-14). Caspases are responsible for breaking down vital structural and functional proteins, leading to the characteristic cytomorphology associated with apoptosis. While multiple molecular pathways (e.g., mitochondrial, death receptor, endoplasmic reticulum pathways) have been identified that lead to the activation of caspases, the mitochondrial (intrinsic) pathway is most associated with neuronal apoptosis. The mitochondrial pathway regulates caspase activity by controlling mitochondrial release of cytochrome c by pro‐ and antiapoptotic members of the Bcl‐2 family of proteins. These proteins interact through dimerization in the mitochondrial membrane. The ratio of proapoptotic (e.g., Bax, Bad) to antiapoptotic (e.g., Bcl‐2, Bcl‐XL) protein levels is a key determinant in regulating cytochrome c release and subsequent caspase activation. For example, high Bax/Bcl‐2 and Bax/Bcl‐XL ratios promote cytochrome c release while low Bax/Bcl‐2 and Bax/Bcl‐XL ratios inhibit cytochrome c release. Downstream of mitochondria, cytochrome c forms a complex with caspase‐9 and Apaf‐1 to form the apoptosome. This complex cleaves procaspase‐3 to form activated caspase‐3, which can initiate cellular disassembly. While caspase‐3 is known as a downstream effector caspase, its activity can still be inhibited by members of the inhibitor‐of‐apoptosis (IAP) protein family (e.g., XIAP); XIAP is itself potentially inhibited by Smac/Diablo, a mitochondrial protein (reviewed [5] [3]).

As noted above, apoptotic activity can be triggered by a broad array of stimuli including oxidative stress (e.g., ischemia, hypoxia), proinflammatory cytokines, excitotoxicity, neurotrophin withdrawal, mitochondrial dysfunction, and abnormal intracellular calcium concentrations. A number of these stimuli can alter Bcl‐2 family protein expression via potent regulatory genes such as p53 and par‐4 in order to promote cytochrome c release and induce caspase‐3 activation. Increased neuronal apoptosis has been demonstrated in classic neurodegenerative disorders including Alzheimer's disease. Interestingly, these disorders are also characterized by alterations in apoptotic regulatory proteins including several Bcl‐2 family proteins and caspases. For example, Bcl‐2 and caspase‐3 are increased in Alzheimer's cortex. These increases are thought to be due to a compensatory upregulation in response to the neurodegenerative process. In contrast, lower Bcl‐2 levels have been reported in frontal cortex in patients with autism, a classic neurodevelopmental disorder. Accumulating data suggest important roles for apoptotic pathways in the pathophysiology of a spectrum of neuropathological disorders (reviewed [5] [3]).

Localized Apoptotic Activity in Synapses and Neurites

Although caspase activation is often considered a precursor to rapid cell death, the emerging concept of synaptic or neuritic apoptosis suggests that apoptotic activation can be localized to synapses or distal neurites without inducing immediate neuronal death or involving the neuronal cell body (Fig. 3). Localized apoptotic mechanisms may lead to the release of cytochrome c from the mitochondria and an increase in the concentration of activated caspase‐3 in a presynaptic terminal that is synapsing on a dendritic spine. Increased caspase‐3 activity results in a localized breakdown of this nerve terminal and its synapse. Subsequently, the postsynaptic dendritic spine retracts and disappears. This process could also begin in the postsynaptic dendritic spine. Although mitochondria are usually not found in dendritic spines, dendritic mitochondria may release cytochrome c which can then diffuse into the dendritic spine. A dendritic spine‐localized increase in caspase‐3 activity could subsequently eliminate the spine. In Alzheimer's disease, this form of synaptic loss is thought to contribute to the initial cognitive decline that predates the onset of large‐scale neuronal death. In the peripheral and central nervous systems, developmental and injury‐induced synapse elimination has been hypothesized to occur via axon retraction after the postsynaptic cell either withholds trophic support or actively promotes synaptic breakdown. Interestingly, caspase‐3 activity has also been associated with normal physiological activity, including synaptic plasticity. For example, caspase‐3 is involved with axonal regeneration associated with retinal growth cone formation, demonstrating roles in both local protein synthesis and degradation. Caspase activity has also been associated with long‐term spatial memory storage (associated with behavioral training) in the rodent hippocampus and has been localized to dendrites, dendritic spines, and axon terminals in the rat forebrain. Collectively, these studies demonstrate that apoptosis localized to synapses and distal dendrites represents a potential mechanism underlying synaptic remodeling and elimination in both physiological and pathological conditions (reviewed [5] [3]).
Neurodegeneration. Figure 3 Illustration of synaptic (neuritic) apoptosis. A pyramidal neuron is depicted with cortical afferents synapsing on its dendrites. Localized apoptotic mechanisms lead to the release of cytochrome c from the mitochondria and an increase in the concentration of activated caspase‐3 in a presynaptic terminal that is synapsing on a dendritic spine. Increased caspase‐3 activity results in a localized breakdown of this nerve terminal and its synapse. Subsequently, the postsynaptic dendritic spine retracts and disappears (Figure modified from Glantz et al. [5] [3]).

Important Mediators of Neurodegeneration

Oxidative Stress

A variety of metabolic pathways generate highly reactive by‐products known as free radicals including hydrogen peroxide, superoxide anions, and hydroxyradicals. These substances can be used by various cells as part of the immune response to serve useful functions such as to combat infectious organisms and neoplastic cells, and to execute cells programmed for death during the normal course of development. In abnormal circumstances such as associated with traumatic and ischemic injury or neurodegenerative diseases such as Alzheimer's and Parkinson's disease, free radicals may be excessively produced, aberrantly controlled, or inadequately scavenged. In such cases, free radicals cause injury as a result of membrane lipid peroxidation, DNA damage, iron accumulation, and protein nitrosylation. Excess free radicals are normally scavenged and inactivated by several endogenous substances such as vitamin E (α‐tocopherol) which can quench lipid peroxidation, superoxide dismutase which scavenges superoxide radicals, and glutathione peroxidase which removes hydrogen peroxide and lipid peroxides.Therefore alterations or deficits in any of these endogenous substances can contribute to and/or initiate neurodegeneration.

Excitotoxic Amino Acids

Excitotoxic amino acids play a deleterious role in a number of neurologic diseases and are known to contribute to neurodegeneration. These compounds are released in response to a wide variety of insults to the CNS and include glutamate, aspartate, and several oxidation products of cysteine and homocysteine. For example, in stroke, excitatory amino acids are released in the penumbra of ischemic lesions and further released when perfusion is restored, and thus are believed to contribute significantly to reperfusion injury. These compounds are also released following traumatic brain injury, during prolonged seizures, and are thought to contribute to the neurotoxicity associated with the amyloid plaques observed in Alzheimer's disease. Overactivation of N‐methyl‐D‐asparate (NMDA) receptors (a subtype of glutamate receptor) by glutamate leads to alterations in a number of signal systems and ion channels activating apoptosis.

Energy Failure and Ion Dysregulation

Neuronal degeneration may result as a consequence of energy failure within mitochondria precipitated by ischemia, free radical damage, and several acquired and genetic disorders of metabolism. For example, mitochondrial energy disruption and neurodegeneration occur in Wernicke's encephalopathy, an acquired metabolic disorder resulting from ethanol abuse and/or thiamine deficiency. Similar neuropathology can be observed in Leigh's syndrome, an inherited neurometabolic disorder in which point mutations in mitochondrial DNA are evident. Friedrich's ataxia, the most common inherited ataxia, is an autosomal recessive disease in which protein aggregates appear to disrupt mitochondrial iron metabolism, leading to abnormal free radical formation and altered energy metabolism. In the cases highlighted above, specific irreversible processes lead to a decrease in high energy phosphates (e.g., ATP, creatine phosphate), possibly leading further to elevated acyl‐CoA levels that inhibit multiple metabolic processes. Local electrolyte (ion) imbalances and/or ion channel dysfunction are also thought to contribute significantly to neurodegenerative processes. Ion changes are commonly among the early events in apoptosis and fact, alterations in calcium homeostasis are among the best‐documented factors in neurodegeneration. Direct evidence of the importance of ion channels in neurodegeneration comes from genetic disorders that affect specific ion channels (i.e., channelopathies). Channelopathies may underlie certain forms of migraine, episodic ataxias, and epilepsy. Indirect evidence that ion dysregulation plays an important role in some forms of neurodegeneration comes from preclinical studies (i.e, stroke models in animals) in which calcium and sodium channel blockers reduce infarct size.

Inflammation

Several lines of evidence indicate that inflammatory processes contribute to the neurodegeneration found in a number of disease states. A common feature in neurodegenerative diseases is microgliosis. Microglia, in addition to releasing oxygen free radicals, also secrete a variety of compounds and substances known to stimulate local inflammation such as inflammatory cytokines, complement and coagulation proteins, as well as binding proteins. As an example, inflammatory factors found in degenerating sites in Alzheimer's disease brains include activated microglia, the cytokines interleukin Il‐1 and Il‐6, an early component of the complement cascade, Clq, as well as acute phase reactants such as C‐reactive protein.

Neurotrophin Support and Altered Cell Signaling

A continuous supply of a variety of polypeptide molecules known as neurotrophic factors (or neurotrophins) is essential to the nervous systems of all vertebrates throughout development as well as in adult life [4]. These important molecules interact with specific receptors and initiate a variety of cellular signaling systems. During the period of target innervation, limiting amounts of neurotrophic factors regulate neuronal numbers by allowing survival of only some of the innervating neurons, the remaining being eliminated by apoptosis. Increasing evidence indicates that several neurotrophic factors also influence the proliferation, survival, and differentiation of precursors of a number of neuronal lineages. In the adult, neurons continue to be dependent on trophic factor support, which may be provided by the target or by the neurons themselves. Altered trophic factor support and cell signaling as a result of excess free radicals or peroxynitrites has been implicated in the neurodegenerative processes associated with several neurologic diseases. Furthermore, the ability of neurotrophins to promote survival of peripheral and central neurons during development and after neuronal damage has stimulated the interest in these molecules as potential therapeutic agents for the treatment of nerve injuries and neurodegenerative diseases. Examples of important (therapeutically relevant, from a neurodegenerative disease standpoint) neurotrophins include nerve growth factor (NGF), and brain derived growth factor (BDNF) (see further discussion below).

Pharmacological Intervention

There are multiple mechanisms known to underlie the neuronal cell damage associated with injury or disease that at least theoretically could be targeted for pharmaceutical intervention. Currently however, there is no clinically available therapeutic agent that can reliably protect the brain from progressive neurodegenerative processes for sustained periods. Due to the extensive amount of preclinical research that has been conducted in recent years, there is a basis for optimism, however, it appears likely that some of these approaches will result in clinically effective therapeutic modalities in the near future. A short overview of some of the investigational approaches to combat neurodegeneration appears below.

Inhibitors of Inflammatory Processes

Inflammatory processes associated with neurodegenerative disease suggest a number of therapeutic targets, including inhibitors of complement activation or cytokines, free radical scavengers, and inhibitors of microglial activation. In retrospective studies, the use of nonsteroidal antiinflammatory drugs (NSAIDS) has been associated with a reduced incidence or slowed progression of Alzheimer disease, indicating a potential for therapeutic use of this class of agent.

Inhibitors of Apoptosis and Growth Factor like Molecules

As indicated earlier, apoptosis is inhibited by certain proteins, such as Bcl‐2 and Bcl‐x. In contrast, Bax and the tumor suppressor protein, p53, have been shown to enhance the onset of apoptosis. Accordingly, drugs which have the ability to enhance the expression of Bcl‐2 and Bcl‐x or to inhibit the expression Bax and p53 could theoretically have the potential to reduce neurodegeneration [5]. Drugs that inhibit apoptosis‐inducing enzymes including caspases may also have a role. The expression of Bcl‐2 and other proteins in this family is also modulated by trophic factors such as NGF and basic fibroblast growth factor (FGF), endogenous neurotrophins which have been shown to block cell death and preserve the phenotype of various cells in the nervous system. NGF is well known to support basal forebrain cholinergic neurons, cells reproducibly ravaged in Alzheimer's disease and known to be critically important for many cognitive processes. Accordingly, there has been interest in using NGF as a therapeutic modality for Alzheimer's disease and potentially other conditions in which cholinergic deficits may be present (e.g., dementia with Lewy bodies). In other investigations, the potential role of trophic molecules in stroke has been evaluated. For example, in animal models of stroke, ischemic damage is reduced following treatment with FGF. Unfortunately, NGF, FGF, as well as most other peptide molecules fail to adequately penetrate the brain from peripheral administration and are thus considerably limited from a therapeutic standpoint. Recent interest has thus focused on low molecular weight growth factor like molecules or small organic molecules that increase the release of growth factors in the brain or increase the expression of growth factor receptors.

Inhibitors of Oxidative Stress

Human trials have evaluated vitamin E, selegeline, and other antioxidant molecules for their ability to prevent or slow the progressive neurodegeneration associated with several neurologic diseases. To date, the data have provided conflicting or equivocal results with some studies showing slightly positive effects and others showing little or no effect. A number of issues require further attention in this area such as the identification of optimal doses of the various antioxidant compounds as well as the evaluation of selected combinations of these agents. These issues are important since specific compounds are known to scavenge or inactivate specific oxidative agents, and thus a single compound would not intuitively be expected to combat free radicals originating from several sources.

Modulators of Glutamate Transmission

Several glutamate antagonists have been or are in the process of being evaluated both preclinically and clinically as neuroprotective agents. For example, MK‐801, an NMDA antagonist, reduces the detrimental effects of excess glutamate (as well as other insults to neurons) in a variety of animal models. Unfortunately the compound is too toxic for use in humans. However, memantine (another NMDA antagonist) is available adjunctively (to be administered with acetylcholinesterase inhibitors) for the treatment of moderate to severe Alzheimer's disease. Riluzole (a drug which inhibits glutamate release), is available clinically for the treatment of amyotrophic lateral sclerosis (ALS) and is somewhat effective in slowing progression. Riluzole has also been shown to reduce infarct size in stroke and brain injury after trauma in animal models and accordingly human studies are anticipated in the near future. Other agents that modulate glutamate receptors such as AMPA antagonists and compounds that interact allosterically at the polyamine and glycine receptor sites are also being evaluated.

Other Investigational Approaches

Other pharmaceutical and molecular therapies are currently being developed to antagonize neurodegenerative processes. For example, compounds designed to prevent toxic reactions of free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), new calcium channel antagonists, as well as compounds that stimulate the expression of antioxidant enzymes such as superoxide dismutase are being developed. Further, the low incidence of cardiovascular disease in those who consume large amounts of omega‐3 fatty acids and their known ability to protect cell membranes from a variety of insults has provided the impetus to evaluate these agents as potential neuroprotectants.

In summary, the steadily increasing size of geriatric populations in developed countries and the resultant increases in age‐related diseases of the brain have provided the impetus for intensive study of the processes underlying neurodegeneration. A better understanding of these processes will likely lead to better methods of treatment not only for progressive memory disorders such as Alzheimer disease, but also for motor disorders such as amyotrophic lateral sclerosis, and cerebrovascular disorders such as stroke.

References

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