Buenz EJ, Rodriguez M, Howe CL.
Disrupted spatial memory is a consequence of picornavirus infection.
Neurobiol Dis. 2006 Nov;24(2):266-73.
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Disrupted spatial memory is a consequence of picornavirus infection
This report investigates the effects of picornavirus infection in the C57BL/6J mouse following intracranial inoculation. The authors report that there was disrupted spatial memory in mice infected with Theiler’s murine encephalomyelitis virus, and that the degree of memory impairment correlated to the extent of hippocampal injury. The human implications of this work are important in that picornaviruses,which are known to be widespread and which include rhinoviruses causing the common cold, poliovirus, and enteroviruses, have neurovirulent potential. As the authors point out, case reports have determined that general encephalitis (Hosoya et al., 1997; Ishigami et al., 2004; McMinn, 2002) and hippocampal damage (Liow et al., 1999; Peatfield, 1987) have been associated with picornavirus infections in the human population. This study could have implications for Alzheimer disease, specifically with regard to the pathogen hypothesis of the disease.
The results from this investigation show that the CA1 region of the hippocampal formation is severely disrupted upon infection with TMEV, and this leads to the loss of spatial memory. This is reminiscent of AD, where the CA1 region is also damaged, leading to dysfunction. Interestingly, picornavirus infection usually is an acute process that results in clearance of the infection; however, over time there may be accumulating subclinical damage that goes unrecognized in the host, especially in humans.
With respect to Alzheimer disease, there are a number of interesting features involving infection that this report invokes. One is the long-term progression that probably revolves around the accumulation of damage that arises in the Alzheimer brain. In this respect, damage to neurons may follow from direct infection and/or from an inflammatory response initiated by the infection. In the current study, the authors don’t directly discuss the process of damage, but because C57BL/6J animals were used in the study, the typical response to infection in these animals is a TH1 response. This response involves the production of proinflammatory molecules that produce damage through the generation of TNFα, IL-1β, as well as the generation of reactive oxygen species. This could result in neuroinflammatory damage in the CA1 region of the hippocampus, something that is clearly detectable in the AD brain. Indeed, this inflammatory response could be a “trigger” mechanism for the ongoing accumulation of damage occurring in AD. This would fit with the proposed “pathogen hypothesis” of AD in which an infection, especially of a chronic/persistent/latent nature, could trigger inflammation, increased production and/or processing of amyloid, breakdown of the blood-brain barrier, etc., to promote neurodegeneration.
In the analysis of the current study, the route of infection was by direct inoculation into brain tissue. Obviously, this is not a natural route of infection, but it does demonstrate the vulnerability of a particular part of the hippocampal formation. Our work on intranasal delivery of Chlamydophila (Chlamydia) pneumoniae to mice (Little et al., 2004) demonstrates that a natural route of infection for a respiratory organism (i.e., through the olfactory neuroepithelium and/or blood-borne) could promote infection in the central nervous system and lead to a damage response as seen with amyloid accumulation. Given that picornaviruses could enter the brain through the olfactory pathways and that they can be particularly virulent in the hippocampus, it is within reason to consider this type of infection to be involved with neurodegenerative processes such as AD. In addition, since analysis of early damage in the Alzheimer brain demonstrates a particular vulnerability of the entorhinal cortex and hippocampus proper, and because of their connections with the olfactory system, an infectious process could provide the stimulus for specific damage in the regions of the brain demonstrating earliest damage. This certainly would address the issue of “selective vulnerability,” an often asked question for why this area of the brain is always damaged in Alzheimer disease.
Now, one could ask why more people aren’t showing Alzheimer-like deficits if infections with ubiquitous organisms like picornaviruses and Chlamydia pneumoniae (Balin et al., 1998; Gerard et al., 2006) are causing the disease. One can use an analogy to another disease process caused by infection to address this question. The prime example is infection with Helicobacter pylori as a causative agent for gastric ulcers, MALT lymphoma, and gastric carcinoma. This organism is highly prevalent in the human population with estimates of infection being as high as 3.5 billion people. However, only approximately 10 percent of those infected actually suffer from one of the diseases noted above. So, this would tell us that exposure alone is not sufficient to cause disease. There must be virulence factors that promote disease in some but not all. Returning to infection in Alzheimer disease, since this is most typically a late-onset disease of older populations, infection virulence may arise through numerous mechanisms. At this time we can only speculate on what those mechanisms may be, but as age is the major risk factor for the disease, how older people deal with infection is a significant issue. Immunosenescence in the older population may be a key factor in this susceptibility to increased infection in the elderly. In addition, the status of the person with regard to nutrition, oxidative stress, and pre-existing disease may also increase their susceptibility.
Recently, a report by Gay et al., 2006, in PNAS demonstrated that infection of an aged host (C57BL/6 mouse) with an avirulent strain of coxsackievirus (CVB3/0) promoted the evolution of the avirulent strain into a virulent strain. These investigators hypothesize that a lowered antioxidant defense mechanism, or an increased level of oxidative stress, could promote a rapid selection of a virulent virus strain due to changes in the viral genome. This work suggests that a process could arise whereby increased susceptibility, morbidity, and mortality from viral infections may occur more readily in the elderly. A similar scenario could arise following infection with Chlamydia pneumoniae in which a more virulent form of the infection may be associated with older people as compared to young or middle-aged people. This could be a significant issue in AD, especially if the organism develops a chronic/persistent infection in the brain which could result in long-term accumulating damage. In this regard, we don’t know if infection in the brains of older animals is more virulent than in the brains of younger animals, although data from our mouse animal model (Little et al., 2005) demonstrates that older animals certainly do not clear infection as well as do younger animals. Future studies that compare isolates of Chlamydia pneumoniae organisms from human AD brain samples with the more typical respiratory isolates will most certainly address this issue. Furthermore, the current emphasis on aging populations and the emergence and re-emergence of infectious disease worldwide mandates that we continue to increase research efforts into the relationships between infection and chronic diseases of aging such as neurodegenerative diseases.
Balin BJ, Gérard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP.
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We would like to add to Brian Balin’s interesting comment that encephalitis and hippocampal damage have been associated with picornaviruses, which could have implications for Alzheimer disease (AD). In fact a number of other viruses—of diverse types—can cause neurological damage, including memory loss, such as the polyoma virus JC (the cause of progressive multifocal leucoencephalopathy), the retrolentivirus HIV, the herpesvirus varicella zoster virus (in post-herpetic neuralgia), and the flavivirus hepatitis C virus (HCV). However, the most common cause of non-epidemic encephalitis is, of course, herpes simplex virus type 1 (HSV1), and herpes simplex encephalitis (HSE) causes memory loss, as well as other neurological deficits, even in those who receive antiviral treatment. The similarity of HSE and AD with respect to the neurological consequences as well as to regions of the brain affected were amongst the main reasons that led us to consider a role for HSV1 in AD and to seek viral DNA in the aged non-HSE brain. We found that it is indeed present—in most of such brains (Jamieson et al., 1991; Jamieson et al., 1992).
Brian asks why most people don’t show AD-like deficits, if ubiquitous organisms like picornaviruses and C. pneumoniae are causing the disease—a question very often asked about our HSV1 results—and he suggests that virulence factors might promote the disease in some people but not others. This seems reasonable, but there is a known major factor in individuals’ response to infection: host genes. We showed that only ApoE4 carriers who harbor HSV1 DNA in brain have a high risk of AD (Itzhaki et al., 1997; Lin et al., 1998) (some 60 percent of sufferers), and that in certain acknowledged viral diseases, such as cold sores (caused by HSV1) (Itzhaki et al., 1997; Lin et al., 1998) and liver damage caused by HCV (Wozniak et al., 2002), ApoE determines outcome of infection, i.e., whether the disease is asymptomatic, mild, or severe. Perhaps the most important additional question is whether a putative etiological agent in AD is normally present in most people, not just systemically but also in the brain. The answer: of all microorganisms, HSV1 is the only one shown so far to reside in a high proportion of elderly brains (Itzhaki and Wozniak, 2006; Jamieson et al., 1991; Jamieson et al., 1992), and so is in a unique position to wreak havoc there (more subtle but more prolonged than in HSE) in certain unfortunate people, perhaps by a mechanism involving β-amyloid or abnormal tau phosphorylation, both of which we have recently linked directly with HSV1 (Wozniak et al., in preparation).
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