key: cord-268776-yfq9oky5
authors: Mattson, Mark P.
title: Infectious agents and age-related neurodegenerative disorders
date: 2003-11-05
journal: Ageing Res Rev
DOI: 10.1016/j.arr.2003.08.005
sha: 
doc_id: 268776
cord_uid: yfq9oky5

As with other organ systems, the vulnerability of the nervous system to infectious agents increases with aging. Several different infectious agents can cause neurodegenerative conditions, with prominent examples being human immunodeficiency virus (HIV-1) dementia and prion disorders. Such infections of the central nervous system (CNS) typically have a relatively long incubation period and a chronic progressive course, and are therefore increasing in frequency as more people live longer. Infectious agents may enter the central nervous system in infected migratory macrophages, by transcytosis across blood–brain barrier cells or by intraneuronal transfer from peripheral nerves. Synapses and lipid rafts are important sites at which infectious agents may enter neurons and/or exert their cytotoxic effects. Recent findings suggest the possibility that infectious agents may increase the risk of common age-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and stroke. While scenarios can be envisioned whereby viruses such as Chlamydia pneumoniae, herpes simplex and influenza promote damage to neurons during aging, there is no conclusive evidence for a major role of these pathogens in neurodegenerative disorders. In the case of stroke, blood vessels may be adversely affected by bacteria or viruses resulting in atherosclerosis.

Other articles in this special issue of Aging Research Reviews describe the alterations in immune function that occur during normal aging that may increase the vulnerability of the elderly to many different types of infectious agents. Bacteria, viruses and unconventional pathogens such as prion proteins can cause inflammatory processes and neuronal degeneration in the central nervous system (CNS). The CNS may be particularly vulnerable to infectious agents during aging ( Fig. 1) because: (1) the bloodbrain barrier and cellular immune mechanisms are compromised during aging such that infectious agents can "hide" in the CNS without being detected by the immune system;

(2) some infectious agents (e.g. herpes virus) can be transferred transcellularly from infected peripheral nerves into the CNS; (3) age-related increases in oxidative stress and impaired energy production can render neurons vulnerable to the toxicity of viral or prion proteins; (4) signaling pathways that promote the survival and plasticity of neurons, such as those activated by neurotrophic factors, may be impaired during aging. Fig. 1 . Mechanisms whereby viruses infect the CNS and cause neuronal dysfunction and death. Two routes of entry of viruses into the CNS are by infection of cells that cross the blood-brain barrier (e.g. cells of the monocyte-macrophage/microglia lineage) and intra-and transneuronal transfer from peripheral neurons. Microglia and neural stem cells appear to be cell types in which viruses may replicate at a high rate; viruses may also infect neurons and astrocytes, but may not replicate in such postmitotic cells. Viruses can produce toxic viral proteins (TVPs) with the HIV-1 proteins gp120 and Tat being exemplary.

Due in part to the low level of immune surveillance the CNS is particularly vulnerable to chronic infection and long-term damage as the result of systemic infection with many relatively common pathogens. Because of the decline in immune function that occurs during aging, and because of an age-related increase in vulnerability of neurons to many different insults, the brain and spinal cord may be hot spots of smoldering infections in the elderly. For example, it is well-established that the elderly are vulnerable to central nervous system damage caused by West Nile virus (Nedry and Mahon, 2003) , Lyme disease (Hayes, 2002) and tuberculosis (Hosoglu et al., 2002) .

Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV-1) virus. HIV-1 infects lymphocytes and impairs their immune function, thereby increasing the risk of several different opportunistic infections and certain types of cancers. Although effective treatments for AIDS, such as protease inhibitor cocktails have been developed, the resulting increase in survival of infected patients has resulted in a dramatic increase in the number of individuals in which serious neurological consequences of HIV-1 infection arise (Gartner, 2000; McArthur et al., 2003) . Dementia is now common in treated AIDS patients and results from degeneration of synapses and neurons in brain regions such as the hippocampus and related limbic and cortical structures. HIV encephalitis also takes a toll on neurons in the basal ganglia-dysfunction and degeneration of neurons in the basal ganglia result in motor dysfunction and may also contribute to cognitive impairment, particularly in older patients infected with HIV (Berger and Arendt, 2000; Nath et al., 2000) . As is the case with Alzheimer's disease (AD), dementia in HIV-infected patients is more severe in those with an E4 allele of apolipoprotein E (Corder et al., 1998) .

The mechanism by which HIV-1 causes dysfunction and degeneration of neurons in the brain is not fully understood. The cells in which HIV-1 replicates in the CNS may include microglia/brain macrophages and neural stem cells (Haughey and Mattson, unpublished data) . HIV-1 does not infect neurons and it is therefore believed that neurons are damaged by HIV-1 proteins released from infected cells. Two such neurotoxic HIV-1 proteins have been identified, namely, the coat protein gp120 and the transcriptional regulator Tat, both of which have been shown to be present in soluble forms in the brains of HIV-1 dementia patients. Both gp120 and Tat can kill cultured neurons and can increase the vulnerability of neurons to excitotoxicity and apoptosis (Haughey and Mattson, 2002) . Patients with HIV dementia exhibit evidence of oxidative damage in their brains including increased amounts of peroxynitrite, 4-hydroxynonenal and protein carbonyls . gp120 and Tat have been shown to increase oxidative stress, and antioxidants can protect cells from the damaging effects of these proteins, suggesting an important role for oxidative damage in the pathogenesis of HIV dementia (Kruman et al., 1998) . Inflammatory cytokines that are known to be increased in the brains of HIV dementia patients (TNF␣, IL1, IFN␥ and Fas/FasL) can induce ceramide production in non-neural cells by increasing the G RTK 7TMR GPI virus Ca2+ Gp120

Tat cholesterol sphingomyelin Ceramide dendrite Fig. 2 . Roles of membrane lipid rafts in infections of the central nervous system. Lipid rafts are microdomains of the plasma membrane in which the outer leaflet of the phospholipid bilayer contains relatively high levels of cholesterol and sphingomyelin. A variety of receptors and associated signal transduction proteins (receptor tyrosine kinases, RTK; seven transmembrane receptors, 7TMR coupled to GTP-binding proteins), and ion channels are concentrated in lipid rafts. Viruses may gain entry to cells by binding to proteins (e.g. GPI-anchored receptors) or lipids in lipid rafts. Lipid rafts may also be regions of membranes that are damaged by cytotoxic viral proteins such as the HIV-1 proteins gp120 and Tat. activity of sphingomylinases (Shi et al., 1998; Wiegmann et al., 1994) . Prominent increases in the pro-inflammatory cytokines TNF␣, IL1, IL2, IL6 and Fas/FasL have been reported in brain and CSF of HIV dementia patients (Wesselingh et al., 1993) . Antiretroviral treatment can dramatically slow cognitive decline and restore the cytokine balance, suggesting that inflammatory products play important roles in HIV associated CNS dysfunction .

Emerging findings suggest that membrane microdomains called lipid rafts play important roles in the pathogenesis of HIV dementia. Lipid rafts are regions of the plasma membrane that have high levels of cholesterol and sphingomyelin, and receptors for many different cytokines and growth factors are concentrated in these membrane microdomains (Fig. 2) . Lipid rafts are believed to be portals through which many different types of viruses, including HIV-1 enter cells (Campbell et al., 2001) . In addition, lipid rafts may be regions of the cell at which gp120 and Tat exert their neurotoxic actions. Activation of cytokine receptors and oxidative stress can induce the production of ceramide from membrane sphingomyelin and ceramide, in turn can trigger a form of programmed cell death called apoptosis. We discovered that levels of ceramide and sphingomyelin are significantly increased in brain tissues and cerebrospinal fluid of patients with HIV dementia . When cultured neurons were exposed to gp120 and Tat, levels of ceramide increased greatly. The ceramide precursor palmitoyl-CoA sensitized neurons to Tat and gp120 toxicities, and an inhibitor of ceramide production protected the neurons, demonstrating a critical role for ceramide in the neurotoxic actions of HIV-1. A better understanding of the roles of lipid rafts in the pathogenesis of HIV-1 dementia may lead to novel approaches for preventing and treating this disorder.

There has been much interest in prion disorders because of their transmissibility among humans and the potential for their transmission from animals, and animal products such as beef, to humans. Prion disorders affect primarily the CNS. Examples include scrapie in sheep, bovine spongiform encephalopathy in cattle, and Kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia in humans (Mastrianni and Roos, 2000; Giese and Kretzschmar, 2001; McKintosh et al., 2003) . These disorders are characterized by the intracellular accumulation of insoluble aggregates of prion protein, abnormal (scrapie) forms (PrPsc) of a normal protein called the cellular prion protein (PrPc). Because prion disorders can be transmitted from one individual to another it was initially assumed that these diseases were caused by a virus. However, intensive investigations failed to identify a virus and the emerging evidence led to the remarkable conclusion that the disease is transmitted by an abnormal form of the prion protein itself. PrPsc adopts a structure that fosters an interaction with PrPc that results in PrPc being converted to the pathogenic PrPsc form (Fig. 3) . In some cases the abnormal prion protein may result from a mutation in the PrPc gene, while in other cases the abnormal conformation of PrPsc may result from posttranslational modifications (Wiessmann, 2002) .

Prion disorders may have a long incubation time and acquired cases of prion disease are more common in older individuals. Prion proteins may damage and kill neurons by inducing oxidative stress, disrupting calcium homeostasis and triggering apoptosis (Haughey and Mattson, 2002) . Inflammatory processes involving microglial activation and production of pro-inflammatory cytokines may also contribute to the pathogenesis of prion disorders (Eikelenboom et al., 2002) . Changes that occur in brain cells during normal aging, including increased oxidative stress and metabolic impairment, may render neurons vulnerable to the toxicity of PrPsc.

It is known that inflammation-like processes occur in the brains of patients with Alzheimer's, Parkinson's (PD) and Huntington's diseases, but whether such inflammatory processes are pathogenic or simply represent responses to neuronal degeneration is unclear. It has been suggested that certain childhood infections may increase the risk of age-related neurodegenerative disorders, although the evidence is as yet meager (Martyn, 1997) . There are certainly a variety of viruses that infect cells in the nervous system and some of these viruses can be retained in neurons for long periods and even for the lifetime of an individual Examples include herpes simplex-1, Sindbis virus, measles and rabies (Kristensson et al., 1996; Griffin, 1998; Schneider-Schaulies et al., 2001; Mettenleiter, 2003 Normal forms of A␤ (soluble A␤) and prion proteins do not self aggregate, whereas in prion disorders and Alzheimer's disease the proteins generate reactive oxygen species (ROS) and acquire abnormal conformations. Genetic factors (e.g. mutations in the genes encoding the prion protein or A␤) and environmental factors (e.g. high caloric intake or folate deficiency) and the aging process may cause or promote formation of pathogenic forms of A␤ and PrPsc. During the process of peptide oligomer and fibril formation, A␤ and PrPsc induce membrane-associated oxidative stress and disrupt membrane ion transporter and channel functions resulting in synaptic and mitochondrial dysfunction and apoptosis. It has recently become evident that autoantibodies against abnormal conformations of A␤ and PrPsc can be generated by the immune systems in patients and in subjects immunized with A␤ or prion peptides. The autoantibodies may promote clearance of the endogenous pathogenic proteins from the brain and/or they may enhance the neurotoxicity of A␤ or PrPsc. transient infections might trigger neurodegenerative cascades when the infection occurs in aged individuals who may be at risk of the disease.

AD is characterized by the accumulation of amyloid ␤-peptide (A␤), synaptic dysfunction and degeneration, and neuronal death in brain regions involved in learning and memory processes (Mattson, 1997a (Mattson, ,b, 2002 . Mutations in three different genes (the amyloid precursor protein, presenilin-1 and presenlin-2), and studies of cultured cells and transgenic mice expressing AD-linked APP and presenilin mutations have provided evidence that a critical event in AD is altered proteolytic processing of APP resulting in increased production of A␤. A␤ may damage neurons and render them vulnerable to excitotoxicity and apoptosis by inducing membrane lipid peroxidation and impairing the function of ion-motive ATPases, glucose and gluatmate transporters, and ion channels (Mattson et al., 1992; Mark et al., 1997; Guo et al., 1998 Guo et al., , 1999a (Fig. 3) . In addition to the degeneration of synapses and neurons that occurs in AD, damage to the oligodendrocytes that myelinate axons in the brain have been documented in mouse models of AD (Pak et al., 2003) . Environmental factors that may increase the risk of AD include a high caloric intake and dietary folate deficiency (Zhu et al., 1999; Kruman et al., 2002a,b) .

Altered immune responses have been documented in studies of AD patients and in animal models and may result, in part, from perturbed calcium signaling in lymphocytes and microglia Lee et al., 2002) . A␤ may play an important role in triggering activation of microglia in AD by a mechanism involving the activation of CD40 (Tan et al., 1999) , and A␤ can also perturb astrocyte function in ways that may impair their ability to communicate with neurons . Peripheral or central stimulation with lipopolysaccharide induces a transient increase in expression of pro-inflammatory cytokines such as TNF, interleukin 1 beta and interleukin 6, and these cytokine changes are associated with microglial activation and altered processing of APP (Brugg et al., 1995; Lee et al., 2002) , suggesting roles of immune responses in neurodegenerative cascades in AD. While it has been proposed that the immune system can be stimulated by immunization with A␤, the specific antibodies produced may determine whether such immunization is beneficial or promotes neuronal degeneration instead .

Systemic infection can result in inflammatory processes in the brain including microglial activation. Infections in the elderly can result in cognitive impairment that outlasts the infection; in patients with AD who encounter a systemic infection, cognitive function can be impaired for several months after the resolution of a systemic infection and the cognitive impairment is preceded by raised serum levels of interleukin 1 beta (Holmes et al., 2003) . Soininen et al. (1993) analyzed circulating immune complexes in the blood of patients with AD and individuals with age-associated memory impairment. AD patients with severe dementia had significantly elevated levels of circulating immune complexes compared with AD patients with mild or moderate disease and to control subjects and individuals with age-associated memory impairment. It is unclear whether the increased immune complexes in severe AD patients contribute to the pathogenic process.

Nucleic acids prepared from postmortem brain tissue samples from AD patients and control subjects were screened by polymerase chain reaction assay for DNA sequences from Chlamydia pneumoniae; brain areas with typical AD-related neuropathology were positive for the organism in 17/19 AD patients, whereas 18/19 control patients were negative (Balin et al., 1998) . The latter study also showed that cultures from affected AD brain tissues were strongly positive for C. pneumoniae, while identically performed analyses of non-AD brain tissues were negative. In a subsequent study by this the same investigators it was reported the C. pneumoniae is present in glial cells in areas of neuropathology in the brains of AD patients (Balin and Appelt, 2001) . The cells in the brains of AD patients that might be infected by C. pneumoniae include vascular endothelial cells and monocytes; these cells may play roles in the inflammatory processes and neuronal degeneration in AD (MacIntyre et al., 2003) . However, a role for C. pneumoniae in AD pathogenesis remains to be established and negative data have been obtained. For example, in a study of centenarians there was no association between C. pneumoniae infection and dementia (Bruunsgaard et al., 2002) .

Dobson and Itzhaki reported that herpes simplex type 1 virus (HSV1) is present in the brain of many elderly people, and that it may be a risk factor for AD, particularly in individuals with the apolipoprotein E4 allele (Dobson and Itzhaki, 1999) . However, in other studies there was no evidence of herpes virus RNA in the hippocampus of demented individuals with extensive neuropathological changes of AD (Deatly et al., 1990) . Finally, in an interesting study it was shown that caregivers of AD patients have significantly poorer immune responses to influenza virus vaccine when compared to age-matched control subjects (Kiecolt-Glaser et al., 1996) , which may result from the chronic stress associated with caregiving leading to increased vulnerability to infection and perhaps to increased vulnerability to age-related neurodegenerative disorders as well.

PD is characterized by degeneration of dopamine-producing neuron in the substantia nigra resulting in progressive impairment of the patient's ability to control their body movements. Most cases of PD are sporadic and the causes are unknown, although rare cases are caused by inherited mutations in ␣-synuclein, Parkin or DJ-1 (Moore et al., 2003) . It is believed that mitochondrial dysfunction and associated ATP depletion and oxidative stress are pivotal and relatively early events in the neurodegenerative process in PD (Duan et al., 1999a) (Fig. 4) . Dopaminergic neurons may die in PD by apoptosis mediated by Par-4 (Duan et al., 1999b) and the tumor suppressor protein p53 (Duan et al., 2002a; Gilman et al., 2003) . Epidemiological and experimental findings suggest a potential role for environmental toxins such as the pesticide rotenone in the pathogenesis of PD, although the data are not yet conclusive (Di Monte et al., 2002) . Dietary factors such as high calorie intake and folate deficiency (Duan and Mattson, 1999; Duan et al., 2002b) and exposure to pesticides and excitotoxins (Lockwood, 2000; Ludolph et al., 2000) may also increase the risk of PD.

Some epidemiological data suggest that influenza A viral infections may increase the risk of PD and may be responsible for the formation of Lewy bodies and the later death of nigral neurons (Takahashi and Yamada, 1999) . Based upon data suggesting that peptic ulcer is more frequent in PD patients and that Helicobacter pylori can cause ulcers, a study was performed to determine whether H. pylori seropositivity was associated with PD (Charlett et al., 1999) . It was shown that siblings of PD patients had an increased probability of H. pylori seropositivity compared to control subjects. In one study there was an increased percentage of teachers and healthcare workers with PD in a large tertiary care movement disorders clinic suggesting the possibility that a high level of exposure to viral or other respiratory infections in these occupations might be a risk factor for PD (Tsui et al., 1999) . The possibility that viruses can induce PD is suggested by studies showing that certain viruses can induce PD-like pathology in rodents. For example, rats infected with Japanese encephalitis virus exhibited neuronal loss with gliosis which was confined mainly to the zona compacta of the substantia nigra (Ogata et al., 1997) .

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of lower and upper motor neurons resulting in progressive paralysis and death. The cause(s) of most Fig. 4 . Cellular and molecular mechanisms responsible for motor dysfunction in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Some rare cases of PD and ALS are caused by mutations. Three genes have been identified in which mutations cause early onset inherited PD (Parkin, ␣-synuclein and DJ-1) and mutations in two genes (Cu/Zn-SOD and Alsin) are known to cause ALS. Insight into the molecular and cellular abnormalities that lead to the dysfunction and death of midbrain dopaminergic neurons in PD and of motor neurons in ALS has come from studies of cultured cells and transgenic mice expressing the disease-causing human genes. In the case of PD, each of the mutations has been linked to abnormal ubiquitin/proteasome-mediated proteolysis, cellular oxidative and metabolic stress and triggering of apoptosis. In the case of ALS, Cu/Zn-SOD mutations cause oxidative stress and disrupt cellular calcium homeostasis. The aging process and environmental factors may perturb the same or similar regulatory systems that are adversely affected by genetic mutations. Synapses are particularly vulnerable to genetic, aging and environmental factors, and are sites where excitotoxic and apoptotic cascades that cause the death of the neurons are initiated. cases of ALS is unknown, but a few cases result from mutations in the gene encoding Cu/Zn-superoxide dismutase. The pathogenic process in ALS involves increased oxidative stress and disruption of cellular calcium homeostasis which may trigger apoptosis (Pedersen et al., 1998 (Pedersen et al., , 2000 Kruman et al., 1999; Guo et al., 2000) (Fig. 4) . Recent findings suggest that abnormalities in lipid metabolism, involving increased levels of ceramides and cholesterol esters, also plays a role in the pathogenesis of ALS (Cutler et al., 2002) .

The possibility that retroviral infection can cause ALS has recently been suggested by studies of HIV-infected patients who developed a rapid progressive ALS-like disorder as the first manifestation of their HIV-infection (Portegies and Cohen, 2002) . The patients stabilized or improved with antiretroviral therapy. Enterovirus RNA has also been detected in the spinal cords of ALS patients, although it remains to be established if such viruses cause the disease (Portegies and Cohen, 2002) . In a study of Gulf War veterans there was a significant association between systemic mycoplasmal infections and ALS (Nicolson et al., 2002) , although it was not established if mycoplasma plays a role in the pathogenesis of ALS or if ALS patients are more susceptible to ALS. The results of another study suggested an association between the risk of ALS and infection with certain enteroviruses and herpes virus (Cermelli et al., 2003) .

Ischemic stroke, a major cause of death and disability in the elderly, occurs when a blood vessel becomes occluded or ruptures. Risk factors for stroke include high calorie/high fat diets, hypertension and physical inactivity (Gorelick, 1995; Yu and Mattson, 1999; Kurth et al., 2002) . Neurons in the brain region normally perfused by the affected blood vessel degenerate after a stroke as the result of decreased glucose and oxygen availability. Ischemic neuronal death involves metabolic compromise, dysregulation of cellular calcium homeostasis and increased oxidative stress Liu et al., 2002) . Activation of microglia and the production of pro-inflammatory cytokines also play an important role in ischemic neuronal death (Bruce et al., 1996; Yu et al., 2000) . In addition to the cascades that result in the death of neurons, several important neuroprotective signaling pathways are activated after a stroke including intercellular signaling involving neurotrophic factors and cytokines, and intracellular pathways involving calcium and transcription factors such as NF-B and CREB (Mattson, 1997b; Mattson et al., 2000; .

Because atherosclerosis is a major antecedent process in stroke, there is evidence that infectious agents that may promote atherosclerosis increase the risk of stroke. There is a growing body of evidence that C. pneumoniae can promote cerebrovascular atherosclerosis and may thereby increase the risk of stroke. Johnston et al. (2001) documented increased C-reactive protein levels and viable C. pneumoniae in atherosclerotic carotid arteries. However, it remains to be established whether C. pneumoniae induces/enhances atherosclerosis or if atherosclerotic plaques provide an environment in which C. pneumoniae accumulates. Similarly, it was reported that C. pneumoniae is present in symptomatic atherosclerotic carotids and that this is associated with increased serum antibodies, inflammation and apoptosis of T cells (Neureiter et al., 2003) . Other systemic bacterial and viral infections may promote stroke by enhancing atherosclerosis and by weakening cerebral blood vessels (Emsley and Tyrrell, 2002) . Acute infectious episodes may increase the risk of acute ischemic stroke in the elderly independently of other predisposing factors (Nencini et al., 2003) . Another infectious agent that may increase the risk of stroke is influenza which is suggested by studies showing that elderly individuals receiving the influenza vaccine have a significantly lower risk of stroke than do those not receiving the vaccine (Meyers, 2003) .

While atherosclerosis is an inflammatory process and is the major pathogenic process that predisposes to stroke, inflammatory mediators also play roles in modifying the neurodegenerative process that occurs as the result of an ischemic stroke. Activated lymphocytes, macrophages and microglia accumulate in ischemic brain tissue after a stroke, and these cells may produce neurotoxic cytokines and excitotoxins. Accordingly, it has been shown that anti-inflammatory drugs can reduce the extent of brain injury in animal models of stroke (Antezana et al., 2003) . Not only is aging a risk factor for infection with agents that may promote atherosclerosis, but older persons who suffer a stroke have a significantly worse outcome-more brain tissue is damaged and recovery of function is limited (Duverger and MacKenzie, 1988) .

The myelinating cells of the central (oligodendrocytes) and peripheral (Schwann cells) nervous systems are vulnerable to being damaged and killed by several viruses (Fazakerley and Walker, 2003) . Progressive multifocal leukoencephalopathy is caused by the infection of oligodendrocytes by JC papovirus and is characterized by slowly progressing dementia, visual problems and ataxia. Subacute sclerosing panencephalitis is caused by the measles virus and is characterized by behavioral changes mental and visual disturbances and ataxia; it is almost always fatal. The damage to oligodendrocytes may result from infection by the virus, exposure to viral proteins and/or an autoimmune response. Certain coronaviruses can also cause demyelination. For example, the mouse hepatitis virus can cause demyelination in the brains of non-human primates and human coronaviruses related to mouse hepatitis virus have been detected in brain tissue samples from patients with multiple sclerosis.

Multiple sclerosis is the most common demyelinating disorder in humans (Cluskey and Ramsden, 2001) .

Although not yet conclusive, accumulating data suggest that infectious agent could be involved in the pathogenesis of multiple sclerosis. Associations between infections with measles virus, parainfluenza virus, canine distemper, human herpes virus-6 and C. pneumoniae have been reported (for review see Steiner et al., 2001) . It is clear that there is an autoimmune component to multiple sclerosis and it is possible that infectious agents may initiate damage to oligodendrocytes or otherwise elicit targeting of oligodendrocytes by the immune system. Because it is well-established that many different viruses can cause demyelination, it will be important to establish which specific viruses play a role in the pathogenesis of multiple sclerosis.

As a result of the large and repetitive ion fluxes associated with membrane depolarization, and neurotransmitter release and receptor activation, synapses are sites at which neurons are subjected to very high levels of oxidative and metabolic stress. Accordingly, synapses have been shown to vulnerable to dysfunction and degeneration in each of the infectious and age-related neurodegenerative disorders described above. Synapses are where excitotoxicity is initiated, a process in which glutamate receptors are overactivated under conditions of oxidative and metabolic stress, resulting in excessive calcium influx (Gilman and Mattson, 2002; Mattson, 2003) . Apoptosis may also be triggered at synapses and, indeed, biochemical cascades can be locally engaged in synapses in experimental models relevant to the pathogenesis of neurodegenerative disorders (Mattson et al., 1998a,b; Duan et al., 1999b; Glazner et al., 2000; Gilman et al., 2003) . Thus, synapses are vulnerable to the kinds of factors that are promoted by infectious agents. For example, the HIV-1 proteins gp120 and Tat induce oxidative stress and promote calcium influx through glutamate receptor channels and voltage-dependent channels which are concentrated in synapses (Haughey and Mattson, 2002) .

In addition to their vulnerability to aging and infectious agents, synapses may play important roles in the propagation of infectious agents in the CNS. Synapses may portals of entry of viruses because cell surface receptors to which the viruses bind are located in lipid rafts which are concentrated in synaptic membranes. For example, putative receptors for botulinum and tetanus toxins are located in synapses (Herreros et al., 1997 (Herreros et al., , 2000 . Some viruses, such as herpes simplex, can be transferred between neurons; this transcellular transfer occurs at synapses and likely involves specific exocytotic and endocytotic mechanisms (Labetoulle et al., 2000) .

High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats

Role of infection in Alzheimer's disease

Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain

HIV dementia: the role of the basal ganglia and dopaminergic systems

Altered neuronal and microglial responses to brain injury in mice lacking TNF receptors

Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain

Proinflammatory cytokines, antibodies to Chlamydia pneumoniae and age-associated diseases in Danish centenarians: is there a link? Scand

Lipid rafts and HIV-1: from viral entry to assembly of progeny virions

Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7

Parkinsonism: siblings share Helicobacter pylori seropositivity and facets of syndrome

Mechanisms of neurodegeneration in amyotrophic lateral sclerosis

HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy

Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in ALS

Human herpes virus infections and Alzheimer's disease

Environmental factors in Parkinson's disease

Herpes simplex virus type 1 and Alzheimer's disease

Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease

Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease

Prostate apoptosis response-4 production in synaptic compartments following apoptotic and excitotoxic insults: evidence for a pivotal role in mitochondrial dysfunction and neuronal degeneration

p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism

Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease

The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age

Neuroinflammation in Alzheimer's disease and prion disease

Inflammation and infection in clinical stroke

Virus demyelination

HIV infection and dementia

Prion-induced neuronal damage-the mechanisms of neuronal destruction in the subacute spongiform encephalopathies

Do apoptotic mechanisms regulate synaptic plasticity and growth-cone motility

p53 is present in synapses where it mediates mitochondrial dysfunction and synaptic degeneration in response to DNA damage, and oxidative and excitotoxic insults

Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis

Stroke prevention

A review of alphavirus replication in neurons

Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a presenilin-1 mutation

Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice

ALS-linked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury

Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120

Alzheimer's amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes

Involvement of perturbed sphingolipid metabolism and ceramide production in the pathogenesis of HIV dementia

Lyme disease

Localization of putative receptors for tetanus toxin and botulinum neurotoxin type A in rat central nervous system

C-terminal half of tetanus toxin fragment C is sufficient for neuronal binding and interaction with a putative protein receptor

Systemic infection

Predictors of outcome in patients with tuberculous meningitis

C-reactive protein levels and viable Chlamydia pneumoniae in carotid artery atherosclerosis

Mitochondrial MnSOD prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation and mitochondrial dysfunction

Chronic stress alters the immune response to influenza virus vaccine in older adults

Rabies: interactions between neurons and viruses. A review of the history of Negri inclusion bodies

ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis

HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress

Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease

Body mass index and the risk of stroke in men

Neuronal pathways for the propagation of herpes simplex virus type 1 from one retina to the other in a murine model

Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain

Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release

Pesticides and parkinsonism: is there an etiological link?

The role of excitotoxicity in ALS-what is the evidence?

Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells

Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation

Infection in childhood and neurological diseases in adult life

The prion diseases

Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives

Neuroprotective signal transduction: relevance to stroke

Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease

Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders

NF-B in neurodegenerative disorders

␤-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity

Evidence for synaptic apoptosis

Amyloid ␤-peptide induces apoptosis-related events in synapses and dendrites

Apoptotic and antiapoptotic mechanisms in stroke

Presenilin mutations and calcium signaling defects in the nervous and immune systems

Human immunodeficiency virus-associated dementia: an evolving disease

Prion diseases

Pathogenesis of neurotropic herpesviruses: role of viral glycoproteins in neuroinvasion and transneuronal spread

Myocardial infarction, stroke, and sudden cardiac death may be prevented by influenza vaccination

A role for the ubiquitin-proteasome system in Parkinson's disease and other neurodegenerative brain amyloidoses

Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia

Autoantibodies to amyloid beta-peptide (Abeta) are increased in Alzheimer's disease patients and Abeta antibodies can enhance Abeta neurotoxicity: implications for disease pathogenesis and vaccine development

West Nile virus: an emerging virus in North America

Acute inflammatory events and ischemic stroke subtypes

Detection of Chlamydia pneumoniae but not of Helicobacter pylori in symptomatic atherosclerotic carotids associated with enhanced serum antibodies, inflammation and apoptosis rate

High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with amyotrophic lateral sclerosis (ALS)

A rat model of Parkinson's disease induced by Japanese encephalitis virus

Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice

Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients

The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis

Possible etiological role retroviruses and enteroviruses in the development of amyotrophic lateral sclerosis

Measles virus interactions with cellular receptors: consequences for viral pathogenesis

Neuronal apoptosis induced by HIV-1 Tat protein and TNF-alpha: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia

Circulating immune complexes in sera from patients with Alzheimer's disease and subjects with age-associated memory impairment

Infection and the etiology and pathogenesis of multiple sclerosis

Viral etiology for Parkinson's disease-a possible role of influenza A virus infection

Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation

Occupational risk factors in Parkinson's disease

Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants

Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia

Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling

Molecular genetics of transmissible spongiform encephalopathies: an introduction

Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism

Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis

Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation